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(PDF) Discovery of New AKT1 Inhibitors by Combination of In silico Structure Based Virtual Screening Approaches and Biological Evaluations
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Herein, we discovered a new set of ligands that inhibit the AKT1, as shown by in vitro binding and cell line studies, using a newly designed virtual screening protocol that combines" /> <meta name="twitter:image" content="http://a.academia-assets.com/images/twitter-card.jpeg" /> <meta property="fb:app_id" content="2369844204" /> <meta property="og:type" content="article" /> <meta property="og:url" content="https://www.academia.edu/52807479/Discovery_of_New_AKT1_Inhibitors_by_Combination_of_In_silico_Structure_Based_Virtual_Screening_Approaches_and_Biological_Evaluations" /> <meta property="og:title" content="Discovery of New AKT1 Inhibitors by Combination of In silico Structure Based Virtual Screening Approaches and Biological Evaluations" /> <meta property="og:image" content="http://a.academia-assets.com/images/open-graph-icons/fb-paper.gif" /> <meta property="og:description" content="AKT1 is emerging as a useful target for treating cancer. Herein, we discovered a new set of ligands that inhibit the AKT1, as shown by in vitro binding and cell line studies, using a newly designed virtual screening protocol that combines" /> <meta property="article:author" content="https://independent.academia.edu/FFratev" /> <meta name="description" content="AKT1 is emerging as a useful target for treating cancer. Herein, we discovered a new set of ligands that inhibit the AKT1, as shown by in vitro binding and cell line studies, using a newly designed virtual screening protocol that combines" /> <title>(PDF) Discovery of New AKT1 Inhibitors by Combination of In silico Structure Based Virtual Screening Approaches and Biological Evaluations</title> <link rel="canonical" href="https://www.academia.edu/52807479/Discovery_of_New_AKT1_Inhibitors_by_Combination_of_In_silico_Structure_Based_Virtual_Screening_Approaches_and_Biological_Evaluations" /> <script async src="https://www.googletagmanager.com/gtag/js?id=G-5VKX33P2DS"></script> <script> window.dataLayer = window.dataLayer || []; function gtag(){dataLayer.push(arguments);} gtag('js', new Date()); gtag('config', 'G-5VKX33P2DS', { cookie_domain: 'academia.edu', send_page_view: false, }); gtag('event', 'page_view', { 'controller': "single_work", 'action': "show", 'controller_action': 'single_work#show', 'logged_in': 'false', 'edge': 'unknown', // Send nil if there is no A/B test bucket, in case some records get logged // with missing data - that way we can distinguish between the two cases. // ab_test_bucket should be of the form <ab_test_name>:<bucket> 'ab_test_bucket': null, }) </script> <script> var $controller_name = 'single_work'; var $action_name = "show"; var $rails_env = 'production'; var $app_rev = 'a68ca24ef94e14dff4960a9c79b38817761055c5'; var $domain = 'academia.edu'; var $app_host = "academia.edu"; var $asset_host = "academia-assets.com"; var $start_time = new Date().getTime(); var $recaptcha_key = "6LdxlRMTAAAAADnu_zyLhLg0YF9uACwz78shpjJB"; var $recaptcha_invisible_key = "6Lf3KHUUAAAAACggoMpmGJdQDtiyrjVlvGJ6BbAj"; var $disableClientRecordHit = false; </script> <script> window.require = { config: function() { return function() {} } } </script> <script> window.Aedu = window.Aedu || {}; window.Aedu.hit_data = null; window.Aedu.serverRenderTime = new Date(1740154204000); window.Aedu.timeDifference = new Date().getTime() - 1740154204000; </script> <script type="application/ld+json">{"@context":"https://schema.org","@type":"ScholarlyArticle","abstract":"AKT1 is emerging as a useful target for treating cancer. Herein, we discovered a new set of ligands that inhibit the AKT1, as shown by in vitro binding and cell line studies, using a newly designed virtual screening protocol that combines structure-based pharmacophore and docking screens. Taking together with the biological data, the combination of structure based pharamcophore and docking methods demonstrated reasonable success rate in identifying new inhibitors (60-70%) proving the success of aforementioned approach. A detail analysis of the ligand-protein interactions was performed explaining observed activities.\u0026amp;amp;amp;lt;br\u0026amp;amp;amp;gt;","author":[{"@context":"https://schema.org","@type":"Person","name":"Filip Fratev","url":"https://independent.academia.edu/FFratev"}],"contributor":[],"dateCreated":"2021-09-19","dateModified":"2024-09-07","headline":"Discovery of New AKT1 Inhibitors by Combination of In silico Structure Based Virtual Screening Approaches and Biological Evaluations","image":"https://attachments.academia-assets.com/69893947/thumbnails/1.jpg","inLanguage":"en","keywords":["Biochemistry and cell biology"],"publisher":{"@context":"https://schema.org","@type":"Organization","name":"American Chemical Society 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Herein, we discovered a new set of ligands that inhibit the AKT1, as shown by in vitro binding and cell line studies, using a newly designed virtual screening protocol that combines structure-based pharmacophore and docking screens. Taking together with the biological data, the combination of structure based pharamcophore and docking methods demonstrated reasonable success rate in identifying new inhibitors (60-70%) proving the success of aforementioned approach. A detail analysis of the ligand-protein interactions was performed explaining observed activities.\u0026lt;br\u0026gt;","publisher":"American Chemical Society (ACS)"},"document_type":"paper","pre_hit_view_count_baseline":null,"quality":"high","language":"en","title":"Discovery of New AKT1 Inhibitors by Combination of In silico Structure Based Virtual Screening Approaches and Biological Evaluations","broadcastable":false,"draft":null,"has_indexable_attachment":true,"indexable":true}}["work"]; window.loswp.workCoauthors = [34268651]; window.loswp.locale = "en"; window.loswp.countryCode = "SG"; window.loswp.cwvAbTestBucket = ""; window.loswp.designVariant = "ds_vanilla"; window.loswp.fullPageMobileSutdModalVariant = "full_page_mobile_sutd_modal"; window.loswp.useOptimizedScribd4genScript = false; window.loginModal = {}; window.loginModal.appleClientId = 'edu.academia.applesignon'; window.userInChina = "false";</script><script defer="" src="https://accounts.google.com/gsi/client"></script><div class="ds-loswp-container"><div class="ds-work-card--grid-container"><div class="ds-work-card--container js-loswp-work-card"><div class="ds-work-card--cover"><div class="ds-work-cover--wrapper"><div class="ds-work-cover--container"><button class="ds-work-cover--clickable js-swp-download-button" data-signup-modal="{"location":"swp-splash-paper-cover","attachmentId":69893947,"attachmentType":"pdf"}"><img alt="First page of “Discovery of New AKT1 Inhibitors by Combination of In silico Structure Based Virtual Screening Approaches and Biological Evaluations”" class="ds-work-cover--cover-thumbnail" src="https://0.academia-photos.com/attachment_thumbnails/69893947/mini_magick20210919-323-sapgra.png?1632045345" /><img alt="PDF Icon" class="ds-work-cover--file-icon" src="//a.academia-assets.com/images/single_work_splash/adobe_icon.svg" /><div class="ds-work-cover--hover-container"><span class="material-symbols-outlined" style="font-size: 20px" translate="no">download</span><p>Download Free PDF</p></div><div class="ds-work-cover--ribbon-container">Download Free PDF</div><div class="ds-work-cover--ribbon-triangle"></div></button></div></div></div><div class="ds-work-card--work-information"><h1 class="ds-work-card--work-title">Discovery of New AKT1 Inhibitors by Combination of In silico Structure Based Virtual Screening Approaches and Biological Evaluations</h1><div class="ds-work-card--work-authors ds-work-card--detail"><a class="ds-work-card--author js-wsj-grid-card-author ds2-5-body-md ds2-5-body-link" data-author-id="34268651" href="https://independent.academia.edu/FFratev"><img alt="Profile image of Filip Fratev" class="ds-work-card--author-avatar" src="//a.academia-assets.com/images/s65_no_pic.png" />Filip Fratev</a></div><div class="ds-work-card--detail"><div class="ds-work-card--work-metadata"><div class="ds-work-card--work-metadata__stat"><span class="material-symbols-outlined" style="font-size: 20px" translate="no">visibility</span><p class="ds2-5-body-sm" id="work-metadata-view-count">…</p></div><div class="ds-work-card--work-metadata__stat"><span class="material-symbols-outlined" style="font-size: 20px" translate="no">description</span><p class="ds2-5-body-sm">23 pages</p></div><div class="ds-work-card--work-metadata__stat"><span class="material-symbols-outlined" style="font-size: 20px" translate="no">link</span><p class="ds2-5-body-sm">1 file</p></div></div><script>(async () => { const workId = 52807479; 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Herein, we discovered a new set of ligands that inhibit the AKT1, as shown by in vitro binding and cell line studies, using a newly designed virtual screening protocol that combines structure-based pharmacophore and docking screens. Taking together with the biological data, the combination of structure based pharamcophore and docking methods demonstrated reasonable success rate in identifying new inhibitors (60-70%) proving the success of aforementioned approach. A detail analysis of the ligand-protein interactions was performed explaining observed activities.&lt;br&gt;</p><div class="ds-work-card--button-container"><button class="ds2-5-button js-swp-download-button" data-signup-modal="{"location":"continue-reading-button--work-card","attachmentId":69893947,"attachmentType":"pdf","workUrl":"https://www.academia.edu/52807479/Discovery_of_New_AKT1_Inhibitors_by_Combination_of_In_silico_Structure_Based_Virtual_Screening_Approaches_and_Biological_Evaluations"}">See full PDF</button><button class="ds2-5-button ds2-5-button--secondary js-swp-download-button" data-signup-modal="{"location":"download-pdf-button--work-card","attachmentId":69893947,"attachmentType":"pdf","workUrl":"https://www.academia.edu/52807479/Discovery_of_New_AKT1_Inhibitors_by_Combination_of_In_silico_Structure_Based_Virtual_Screening_Approaches_and_Biological_Evaluations"}"><span class="material-symbols-outlined" style="font-size: 20px" translate="no">download</span>Download PDF</button></div><div class="ds-signup-banner-trigger-container"><div class="ds-signup-banner-trigger ds-signup-banner-trigger-control"></div></div><div class="ds-signup-banner ds-signup-banner-control"><div id="ds-signup-banner-close-button"><button class="ds2-5-button ds2-5-button--secondary ds2-5-button--inverse"><span class="material-symbols-outlined" style="font-size: 20px" translate="no">close</span></button></div><div class="ds-signup-banner-ctas"><img src="//a.academia-assets.com/images/academia-logo-capital-white.svg" /><h4 class="ds2-5-heading-serif-sm">Sign up for access to the world's latest research</h4><button class="ds2-5-button ds2-5-button--inverse ds2-5-button--full-width js-swp-download-button" data-signup-modal="{"location":"signup-banner"}">Sign up for free<span class="material-symbols-outlined" style="font-size: 20px" translate="no">arrow_forward</span></button></div><div class="ds-signup-banner-divider"></div><div class="ds-signup-banner-reasons"><div class="ds-signup-banner-reasons-item"><span class="material-symbols-outlined" style="font-size: 24px" translate="no">check</span><span>Get notified about relevant papers</span></div><div class="ds-signup-banner-reasons-item"><span class="material-symbols-outlined" style="font-size: 24px" translate="no">check</span><span>Save papers to use in your research</span></div><div class="ds-signup-banner-reasons-item"><span class="material-symbols-outlined" style="font-size: 24px" translate="no">check</span><span>Join the discussion with peers</span></div><div class="ds-signup-banner-reasons-item"><span class="material-symbols-outlined" style="font-size: 24px" translate="no">check</span><span>Track your impact</span></div></div></div><script>(() => { // Set up signup banner show/hide behavior: // 1. 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To search for new inhibitors of Akt kinase, we performed a structure-based virtual screening using the DOCK 4.0 program and the X-ray crystal structure of human Akt kinase. From the virtual screening, 48 compounds were selected and subjected to the Akt kinase inhibition assay. Twenty-six of the test compounds showed more potent inhibitory effects on Akt kinase than the reference compound, H-89. These 26 compounds were further evaluated for their cytotoxicity against HCT-116 human colon cancer cells and HEK-293 normal human embryonic kidney cells. Twelve compounds were found to display more potent or comparable cytotoxic activity compared to compound H-89 against HCT-116 colon cancer cells. The best results were obtained with Compounds a46 and a48 having IC50 values (for HCT-116) of 11.1 and 9.5 µM, respectively, and selectivity indices (IC50 for HEK-293/IC50 f...</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Discovery of Akt kinase inhibitors through structure-based virtual screening and their evaluation as potential anticancer agents","attachmentId":93801306,"attachmentType":"pdf","work_url":"https://www.academia.edu/90162311/Discovery_of_Akt_kinase_inhibitors_through_structure_based_virtual_screening_and_their_evaluation_as_potential_anticancer_agents","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/90162311/Discovery_of_Akt_kinase_inhibitors_through_structure_based_virtual_screening_and_their_evaluation_as_potential_anticancer_agents"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="1" data-entity-id="90162323" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/90162323/Article_Discovery_of_Akt_Kinase_Inhibitors_through_Structure_Based_Virtual_Screening_and_Their_Evaluation_as_Potential_Anticancer_Agents">Article Discovery of Akt Kinase Inhibitors through Structure-Based Virtual Screening and Their Evaluation as Potential Anticancer Agents</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="33306345" href="https://independent.academia.edu/TachunCheng">Ta-chun Cheng</a></div><p class="ds-related-work--metadata ds2-5-body-xs">2016</p><p class="ds-related-work--abstract ds2-5-body-sm">Abstract: Akt acts as a pivotal regulator in the PI3K/Akt signaling pathway and represents a potential drug target for cancer therapy. To search for new inhibitors of Akt kinase, we performed a structure-based virtual screening using the DOCK 4.0 program and the X-ray crystal structure of human Akt kinase. From the virtual screening, 48 compounds were selected and subjected to the Akt kinase inhibition assay. Twenty-six of the test compounds showed more potent inhibitory effects on Akt kinase than the reference compound, H-89. These 26 compounds were further evaluated for their cytotoxicity against HCT-116 human colon cancer cells and HEK-293 normal human embryonic kidney cells. Twelve compounds were found to display more potent or comparable cytotoxic activity compared</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Article Discovery of Akt Kinase Inhibitors through Structure-Based Virtual Screening and Their Evaluation as Potential Anticancer Agents","attachmentId":93801321,"attachmentType":"pdf","work_url":"https://www.academia.edu/90162323/Article_Discovery_of_Akt_Kinase_Inhibitors_through_Structure_Based_Virtual_Screening_and_Their_Evaluation_as_Potential_Anticancer_Agents","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/90162323/Article_Discovery_of_Akt_Kinase_Inhibitors_through_Structure_Based_Virtual_Screening_and_Their_Evaluation_as_Potential_Anticancer_Agents"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="2" data-entity-id="41430629" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/41430629/Combining_ligand_and_structure_based_in_silico_methods_for_the_identification_of_natural_product_based_inhibitors_of_Akt1">Combining ligand‑ and structure‑based in silico methods for the identification of natural product‑based inhibitors of Akt1</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="3564599" href="https://iiim-in.academia.edu/ManasRanjan">Manas Ranjan</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Molecular Diversity, 2019</p><p class="ds-related-work--abstract ds2-5-body-sm">The traditional method of drug discovery process has been surpassed by a rational approach where computer-aided drug designing plays a vital role in the identification of leads from large compound databases. Further, natural products have an important role in drug discovery as these have been the source of most active ingredients of medicines. Herein, in silico structure- and ligand-based approaches have been applied to screen in-house IIIM natural product repository for Akt1 (serine/ threonine protein kinases) which is a well-known therapeutic target for cancer due to its overexpression and preventing the cells from undergoing apoptosis. Combined ligand-based and structure-based strategies were applied on to the existing library comprising of about 700 pure natural products, and the compounds identified from screening were biologically evaluated for Akt1 inhibition using Akt1 kinase activity assay. Fourteen promising compounds showed significant inhibition at 500 nM through in vitro screening, and from them, eight were new for Akt1 inhibition. Through the MD studies of Akt1 with the most active compound IN00145, it was inferred that Lys179, Glu191, Glu228, Ala230, Glu234 and Asp292 are the important amino acid residues which provide stability to the Akt1-IN00145 complex. Lead optimization studies were also performed around the actives to design better and selective inhibitors for Akt1. The results emphasized the successful application of virtual screening to identify new Akt1 inhibitor scaffolds that can be developed into a drug candidate in drug discovery programme.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Combining ligand‑ and structure‑based in silico methods\r\nfor the identification of natural product‑based inhibitors of Akt1","attachmentId":61609706,"attachmentType":"pdf","work_url":"https://www.academia.edu/41430629/Combining_ligand_and_structure_based_in_silico_methods_for_the_identification_of_natural_product_based_inhibitors_of_Akt1","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/41430629/Combining_ligand_and_structure_based_in_silico_methods_for_the_identification_of_natural_product_based_inhibitors_of_Akt1"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="3" data-entity-id="112314431" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/112314431/Ligand_based_modeling_of_Akt3_lead_to_potent_dual_Akt1_Akt3_inhibitor">Ligand-based modeling of Akt3 lead to potent dual Akt1/Akt3 inhibitor</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="39036346" href="https://hejab.academia.edu/MahmoudAlShaer">Mahmoud A Al-Sha'er</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Journal of Molecular Graphics & Modelling, 2018</p><p class="ds-related-work--abstract ds2-5-body-sm">Akt1 and Akt3 are important serine/threonine-specific protein kinases involved in G2 phase required by cancer cells to maintain cell cycle and to prevent cell death. Accordingly, inhibitors of these kinases should have potent anti-cancer properties. This prompted us to use pharmacophore/QSAR modeling to identify optimal binding models and physicochemical descriptors that explain bioactivity variation within a set of 74 diverse Akt3 inhibitors. Two successful orthogonal pharmacophores were identified and further validated using receiver operating characteristic (ROC) curve analyses. The pharmacophoric models and associated QSAR equation were applied to screen the national cancer institute (NCI) list of compounds for new Akt3 inhibitors. Six hits showed significant experimental anti-Akt3 IC 50 values, out of which one compound exhibited dual low micromolar anti-Akt1 and anti-Akt3 inhibitory profiles.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Ligand-based modeling of Akt3 lead to potent dual Akt1/Akt3 inhibitor","attachmentId":109582356,"attachmentType":"pdf","work_url":"https://www.academia.edu/112314431/Ligand_based_modeling_of_Akt3_lead_to_potent_dual_Akt1_Akt3_inhibitor","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/112314431/Ligand_based_modeling_of_Akt3_lead_to_potent_dual_Akt1_Akt3_inhibitor"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="4" data-entity-id="18912409" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/18912409/Evaluation_of_Novel_Akt1_Inhibitors_as_Anticancer_Agents_using_Virtual_Co_crystallized_Pharmacophore_Generation">Evaluation of Novel Akt1 Inhibitors as Anticancer Agents using Virtual Co-crystallized Pharmacophore Generation</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="39036346" href="https://hejab.academia.edu/MahmoudAlShaer">Mahmoud A Al-Sha'er</a></div><p class="ds-related-work--abstract ds2-5-body-sm">The pharmacophoric features of the virtual co-crystallized protein of 17 Akt1 proteins were downloaded from the protein data bank, and explored to end up with 132 generated pharmacophores that had been evaluated using the decoy list composed of 1724 compounds. The areas under the curve of the Receiver-Operating Characteristic (ROC-AUC) were sorted, and the highest ranked pharmacophore 3MV5_2_01 was selected to be used as a searching tool in the National Cancer Institute (NCI) database. The captured hits were mapped based on successful hypotheses and the best fitted compounds were selected. The inhibition of Akt1 was measured and expressed as a percentage of inhibition. 24 out of the 40 compounds showed inhibition of Akt1, out of which 13 compounds showed more than 50% inhibition. Compound 1 showed 93.3% inhibition at 100 µM concentration. To confirm the inhibition of Akt1 phosphorylation, MCF10A cell line was co-treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) and 100 µM of each of the most potent 13 Akt inhibitors (1-13). It was found that compounds 1 exert 91.6% inhibition of Akt1 phosphorylation in MCF10A cell line.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Evaluation of Novel Akt1 Inhibitors as Anticancer Agents using Virtual Co-crystallized Pharmacophore Generation","attachmentId":40324948,"attachmentType":"pdf","work_url":"https://www.academia.edu/18912409/Evaluation_of_Novel_Akt1_Inhibitors_as_Anticancer_Agents_using_Virtual_Co_crystallized_Pharmacophore_Generation","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/18912409/Evaluation_of_Novel_Akt1_Inhibitors_as_Anticancer_Agents_using_Virtual_Co_crystallized_Pharmacophore_Generation"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="5" data-entity-id="49638776" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/49638776/3D_QSAR_modeling_molecular_docking_and_quantum_mechanical_approaches_to_identify_pleckstrin_homology_domain_of_new_AKT1_inhibitors">3D-QSAR modeling, molecular docking and quantum mechanical approaches to identify pleckstrin homology domain of new AKT1 inhibitors</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="164354921" href="https://independent.academia.edu/CMeganathan">Chandrasekaran Meganathan</a></div><p class="ds-related-work--metadata ds2-5-body-xs">7TH NATIONAL CONFERENCE ON HIERARCHICALLY STRUCTURED MATERIALS (NCHSM-2019)</p><p class="ds-related-work--abstract ds2-5-body-sm">The Atom-based 3D-QSAR models have been generated, to identify the essential structural features required for these AKT1 inhibitors using the PHASE module of Schrodinger. A pharmacophore hypothesis contained five features such as one hydrogen bond acceptors, two hydrogen bond donors and two aromatic rings gives a best atom-based 3D-QSAR model. The obtained 3D-QSAR model had good statistical predictive values, cross validated correlation coefficient, Fisher ratio and Pearson's value. Further the predictability of the pharmacophore model was validated using test set prediction such as 2 pred R and rm 2 metrics. Moreover, this validated pharmacophore model was used as a 3D query to screen the compounds from NCI and ZINC database. The resultant hit compounds were filtered by Lipinski's rule of five as well as the ADME properties. The molecular docking study was carried out to explore the suitable binding capabilities of compounds in the AKT1 active site. Further to confirm the inhibitor potencies, we have calculated the highest occupied molecular orbital, lowest unoccupied molecular orbital and energy gap values for hit compounds. Finally, two hit molecules were selected as novel hit molecules based on good molecular interactions, docking score and electronic properties.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"3D-QSAR modeling, molecular docking and quantum mechanical approaches to identify pleckstrin homology domain of new AKT1 inhibitors","attachmentId":67940152,"attachmentType":"pdf","work_url":"https://www.academia.edu/49638776/3D_QSAR_modeling_molecular_docking_and_quantum_mechanical_approaches_to_identify_pleckstrin_homology_domain_of_new_AKT1_inhibitors","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/49638776/3D_QSAR_modeling_molecular_docking_and_quantum_mechanical_approaches_to_identify_pleckstrin_homology_domain_of_new_AKT1_inhibitors"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="6" data-entity-id="9644216" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/9644216/Computational_Insights_into_the_Inhibitory_Mechanism_of_Human_AKT1_by_an_Orally_Active_Inhibitor_MK_2206">Computational Insights into the Inhibitory Mechanism of Human AKT1 by an Orally Active Inhibitor, MK-2206</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="22999475" href="https://independent.academia.edu/TonaQueHay">Tona Que Hay</a></div><p class="ds-related-work--abstract ds2-5-body-sm">The AKT signaling pathway has been identified as an important target for cancer therapy. Among small-molecule inhibitors of AKT that have shown tremendous potential in inhibiting cancer, MK-2206 is a highly potent, selective and orally active allosteric inhibitor. Promising preclinical anticancer results have led to entry of MK-2206 into Phase I/II clinical trials. Despite such importance, the exact binding mechanism and the molecular interactions of MK-2206 with human AKT are not available. The current study investigated the exact binding mode and the molecular interactions of MK-2206 with human AKT isoforms using molecular docking and (un)binding simulation analyses. The study also involved the docking analyses of the structural analogs of MK-2206 to AKT1 and proposed one as better inhibitor. The Dock was used for docking simulations of MK-2206 into the allosteric site of AKT isoforms. The Ligplot+ was used for analyses of polar and hydrophobic interactions between AKT isoforms and the ligands. The MoMa-LigPath web server was used to simulate the ligand (un)binding from the binding site to the surface of the protein. In the docking and (un)binding simulation analyses of MK-2206 with human AKT1, the Trp-80 was the key residue and showed highest decrease in the solvent accessibility, highest number of hydrophobic interactions, and the most consistent involvement in all (un)binding simulation phases. The number of molecular interactions identified and calculated binding energies and dissociation constants from the co-complex structures of these isoforms, clearly explained the varying affinity of MK-2206 towards these isoforms. The (un)binding simulation analyses identified various additional residues which despite being away from the binding site, play important role in initial binding of the ligand. Thus, the docking and (un)binding simulation analyses of MK-2206 with AKT isoforms and its structure analogs will provide a suitable model for studying drug-protein interaction and will help in designing better drugs.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Computational Insights into the Inhibitory Mechanism of Human AKT1 by an Orally Active Inhibitor, MK-2206","attachmentId":35844709,"attachmentType":"pdf","work_url":"https://www.academia.edu/9644216/Computational_Insights_into_the_Inhibitory_Mechanism_of_Human_AKT1_by_an_Orally_Active_Inhibitor_MK_2206","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/9644216/Computational_Insights_into_the_Inhibitory_Mechanism_of_Human_AKT1_by_an_Orally_Active_Inhibitor_MK_2206"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="7" data-entity-id="10725668" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/10725668/A_comprehensive_structure_activity_analysis_of_protein_kinase_B_alpha_Akt1_inhibitors">A comprehensive structure–activity analysis of protein kinase B-alpha (Akt1) inhibitors</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="26154355" href="https://independent.academia.edu/SudhirKulkarni7">Sudhir Kulkarni</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Journal of Molecular Graphics & Modelling, 2010</p><p class="ds-related-work--abstract ds2-5-body-sm">Protein kinase B (PKB, also known as Akt) belongs to the AGC subfamily of the protein kinase superfamily. Akt1 has been reported as a central player in regulation of metabolism, cell survival, motility, transcription and cell-cycle progression, among the signalling proteins that respond to a large variety of signals. In this study an attempt was made to understand structural requirements for Akt1 inhibition using conventional QSAR, k-nearest neighbour QSAR and novel GQSAR methods. With this intention, a wide variety of structurally diverse Akt1 inhibitors were collected from various literature reports. The conventional QSAR analyses revealed the key role of Baumann's alignment independent topological descriptors along with other descriptors such as the number of hydrogen bond acceptors, hydrogen bond donors, rotatable bonds and aromatic oxygen (SaaOcount) along with molecular branching (chi3Cluster), alkene carbon atom type (SdsCHE-index) in governing activity variation. Further, the GQSAR analyses show that chemical variations like presence of hetero-aromatic ring, flexibility, polar surface area and fragment length present in the hinge binding fragment (in the present case fragment D) are highly influential for achieving highly potent Akt1 inhibitors. In addition, this study resulted in a k-nearest neighbour classification model with three descriptors suggesting the key role of oxygen (SssOE-index) and aromatic carbon (SaaCHE-index and SaasCE-index) atoms electro-topological environment that differentiate molecules binding to Akt1 kinase or PH domain. The developed models are interpretable, with good statistical and predictive significance, and can be used for guiding ligand modification for the development of potential new Akt1 inhibitors.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"A comprehensive structure–activity analysis of protein kinase B-alpha (Akt1) inhibitors","attachmentId":47173265,"attachmentType":"pdf","work_url":"https://www.academia.edu/10725668/A_comprehensive_structure_activity_analysis_of_protein_kinase_B_alpha_Akt1_inhibitors","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/10725668/A_comprehensive_structure_activity_analysis_of_protein_kinase_B_alpha_Akt1_inhibitors"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="8" data-entity-id="7969851" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/7969851/Discovery_of_a_novel_protein_kinase_B_inhibitor_by_structure_based_virtual_screening">Discovery of a novel protein kinase B inhibitor by structure-based virtual screening</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="15203996" href="https://independent.academia.edu/Narendersingh16">Narender singh</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Bioorganic & Medicinal Chemistry Letters, 2009</p><p class="ds-related-work--abstract ds2-5-body-sm">Protein kinase B (PKB/AKT) is a promising and attractive therapeutic target in anticancer drug development. Herein, we report the findings of virtual screening for novel ATP-competitive inhibitors of AKT-2 using 2D-and 3D-similarity searching and sequential molecular docking with two crystal structures of AKT-2. Our multistep approach led to the identification of a low micromolar AKT-2 inhibitor (IC 50 = 1.5 lM) with a novel scaffold. The experimentally validated inhibitor represents the starting point for an optimization program.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Discovery of a novel protein kinase B inhibitor by structure-based virtual screening","attachmentId":48269650,"attachmentType":"pdf","work_url":"https://www.academia.edu/7969851/Discovery_of_a_novel_protein_kinase_B_inhibitor_by_structure_based_virtual_screening","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/7969851/Discovery_of_a_novel_protein_kinase_B_inhibitor_by_structure_based_virtual_screening"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="9" data-entity-id="17477121" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/17477121/Synthesis_and_structure_based_optimization_of_novel_Akt_inhibitors">Synthesis and structure based optimization of novel Akt inhibitors</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="37234347" href="https://independent.academia.edu/ShaughnessyRobinson">Shaughnessy Robinson</a><span>, </span><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="37450351" href="https://independent.academia.edu/JayvardhanPandit">Jayvardhan Pandit</a><span>, </span><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="51229528" href="https://independent.academia.edu/ShefaliKakar">Shefali Kakar</a><span>, </span><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="37650359" href="https://independent.academia.edu/FrancisRajamohan">Francis Rajamohan</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Bioorganic & Medicinal Chemistry Letters, 2008</p><p class="ds-related-work--abstract ds2-5-body-sm">Based on a high throughput screening hit, pyrrolopyrimidine inhibitors of the Akt kinase are explored. X-ray co-crystal structures of two lead series results in the understanding of key binding interactions, the design of new lead series, and enhanced potency. The syntheses of these series and their biological activities are described. Spiroindoline 13j is found to have an Akt1 kinase IC 50 of 2.4 ± 0.6 nM, Akt cell potency of 50 ± 19 nM, and provides 68% inhibition of tumor growth in a mouse xenograft model (50 mg/kg, qd, po).</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Synthesis and structure based optimization of novel Akt inhibitors","attachmentId":39532028,"attachmentType":"pdf","work_url":"https://www.academia.edu/17477121/Synthesis_and_structure_based_optimization_of_novel_Akt_inhibitors","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/17477121/Synthesis_and_structure_based_optimization_of_novel_Akt_inhibitors"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div></div></div><div class="ds-sticky-ctas--wrapper js-loswp-sticky-ctas hidden"><div class="ds-sticky-ctas--grid-container"><div class="ds-sticky-ctas--container"><button class="ds2-5-button js-swp-download-button" data-signup-modal="{"location":"continue-reading-button--sticky-ctas","attachmentId":69893947,"attachmentType":"pdf","workUrl":null}">See full PDF</button><button class="ds2-5-button ds2-5-button--secondary js-swp-download-button" data-signup-modal="{"location":"download-pdf-button--sticky-ctas","attachmentId":69893947,"attachmentType":"pdf","workUrl":null}"><span class="material-symbols-outlined" style="font-size: 20px" translate="no">download</span>Download PDF</button></div></div></div><div class="ds-below-fold--grid-container"><div class="ds-work--container js-loswp-embedded-document"><div class="attachment_preview" data-attachment="Attachment_69893947" style="display: none"><div class="js-scribd-document-container"><div class="scribd--document-loading js-scribd-document-loader" style="display: block;"><img alt="Loading..." src="//a.academia-assets.com/images/loaders/paper-load.gif" /><p>Loading Preview</p></div></div><div style="text-align: center;"><div class="scribd--no-preview-alert js-preview-unavailable"><p>Sorry, preview is currently unavailable. You can download the paper by clicking the button above.</p></div></div></div></div><div class="ds-sidebar--container js-work-sidebar"><div class="ds-related-content--container"><h2 class="ds-related-content--heading">Related papers</h2><div class="ds-related-work--container js-related-work-sidebar-card" data-collection-position="0" data-entity-id="115063681" data-sort-order="default"><a class="ds-related-work--title js-related-work-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/115063681/In_search_of_AKT_kinase_inhibitors_as_anticancer_agents_structure_based_design_docking_and_molecular_dynamics_studies_of_2_4_6_trisubstituted_pyridines">In search of AKT kinase inhibitors as anticancer agents: structure-based design, docking, and molecular dynamics studies of 2,4,6-trisubstituted pyridines</a><div class="ds-related-work--metadata"><a class="js-related-work-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="36308944" href="https://unam.academia.edu/AliciaHern%C3%A1ndezcampos">Alicia Hernández-Campos</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Journal of Biomolecular Structure & Dynamics, 2017</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"In search of AKT kinase inhibitors as anticancer agents: structure-based design, docking, and molecular dynamics studies of 2,4,6-trisubstituted pyridines","attachmentId":111581368,"attachmentType":"pdf","work_url":"https://www.academia.edu/115063681/In_search_of_AKT_kinase_inhibitors_as_anticancer_agents_structure_based_design_docking_and_molecular_dynamics_studies_of_2_4_6_trisubstituted_pyridines","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-related-work-grid-card-view-pdf" href="https://www.academia.edu/115063681/In_search_of_AKT_kinase_inhibitors_as_anticancer_agents_structure_based_design_docking_and_molecular_dynamics_studies_of_2_4_6_trisubstituted_pyridines"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-related-work-sidebar-card" data-collection-position="1" data-entity-id="20904873" data-sort-order="default"><a class="ds-related-work--title js-related-work-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/20904873/Novel_chemical_scaffolds_of_the_tumor_marker_AKR1B10_inhibitors_discovered_by_3D_QSAR_pharmacophore_modeling">Novel chemical scaffolds of the tumor marker AKR1B10 inhibitors discovered by 3D QSAR pharmacophore modeling</a><div class="ds-related-work--metadata"><a class="js-related-work-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="42037756" href="https://independent.academia.edu/JungKeunSuh">Jung-Keun Suh</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Acta pharmacologica Sinica, 2015</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Novel chemical scaffolds of the tumor marker AKR1B10 inhibitors discovered by 3D QSAR pharmacophore modeling","attachmentId":41623772,"attachmentType":"pdf","work_url":"https://www.academia.edu/20904873/Novel_chemical_scaffolds_of_the_tumor_marker_AKR1B10_inhibitors_discovered_by_3D_QSAR_pharmacophore_modeling","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-related-work-grid-card-view-pdf" href="https://www.academia.edu/20904873/Novel_chemical_scaffolds_of_the_tumor_marker_AKR1B10_inhibitors_discovered_by_3D_QSAR_pharmacophore_modeling"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-related-work-sidebar-card" data-collection-position="2" data-entity-id="10297819" data-sort-order="default"><a class="ds-related-work--title js-related-work-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/10297819/AKT_crystal_structure_and_AKT_specific_inhibitors">AKT crystal structure and AKT-specific inhibitors</a><div class="ds-related-work--metadata"><a class="js-related-work-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="25230482" href="https://independent.academia.edu/chandrakumar20">chandra kumar</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Oncogene, 2005</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"AKT crystal structure and AKT-specific inhibitors","attachmentId":47447995,"attachmentType":"pdf","work_url":"https://www.academia.edu/10297819/AKT_crystal_structure_and_AKT_specific_inhibitors","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-related-work-grid-card-view-pdf" href="https://www.academia.edu/10297819/AKT_crystal_structure_and_AKT_specific_inhibitors"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div 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