{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T15:35:58Z","timestamp":1777304158832,"version":"3.51.4"},"reference-count":43,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2022,8,9]],"date-time":"2022-08-09T00:00:00Z","timestamp":1660003200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Start-up Funds for Doctoral Research of Northwest Normal University of China","award":["202103101601"],"award-info":[{"award-number":["202103101601"]}]},{"name":"Start-up Funds for Doctoral Research of Northwest Normal University of China","award":["202103101604"],"award-info":[{"award-number":["202103101604"]}]},{"name":"Start-up Funds for Doctoral Research of Northwest Normal University of China","award":["2022QB-032"],"award-info":[{"award-number":["2022QB-032"]}]},{"name":"Start-up Funds for Doctoral Research of Northwest Normal University of China","award":["NWNU-LKQN2021-08"],"award-info":[{"award-number":["NWNU-LKQN2021-08"]}]},{"name":"Young Doctor Fund Project of Education Department of Gansu Province","award":["202103101601"],"award-info":[{"award-number":["202103101601"]}]},{"name":"Young Doctor Fund Project of Education Department of Gansu Province","award":["202103101604"],"award-info":[{"award-number":["202103101604"]}]},{"name":"Young Doctor Fund Project of Education Department of Gansu Province","award":["2022QB-032"],"award-info":[{"award-number":["2022QB-032"]}]},{"name":"Young Doctor Fund Project of Education Department of Gansu Province","award":["NWNU-LKQN2021-08"],"award-info":[{"award-number":["NWNU-LKQN2021-08"]}]},{"name":"Project for Enhancing the Research Capability of Young Teachers in Northwest Normal University","award":["202103101601"],"award-info":[{"award-number":["202103101601"]}]},{"name":"Project for Enhancing the Research Capability of Young Teachers in Northwest Normal University","award":["202103101604"],"award-info":[{"award-number":["202103101604"]}]},{"name":"Project for Enhancing the Research Capability of Young Teachers in Northwest Normal University","award":["2022QB-032"],"award-info":[{"award-number":["2022QB-032"]}]},{"name":"Project for Enhancing the Research Capability of Young Teachers in Northwest Normal University","award":["NWNU-LKQN2021-08"],"award-info":[{"award-number":["NWNU-LKQN2021-08"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Pictilisib (GDC-0941) is a well-known dual inhibitor of class I PI3K and mTOR and is presently undergoing phase 2 clinical trials for cancer treatment. The present work investigated the dynamic behaviors and interaction mechanism between GDC-0941 and human serum albumin (HSA). Molecular docking and MD trajectory analyses revealed that GDC-0941 bound to HSA and that the binding site was positioned in subdomain IIA at Sudlow\u2019s site I of HSA. The fluorescence intensity of HSA was strongly quenched by GDC-0941, and results showed that the HSA\u2013GDC-0941 interaction was a static process caused by ground-state complex formation. The association constant of the HSA\u2013GDC-0941 complex was approximately 105 M\u22121, reflecting moderate affinity. Thermodynamic analysis conclusions were identical with MD simulation results, which revealed that van der Waals interactions were the vital forces involved in the binding process. CD, synchronous, and 3D fluorescence spectroscopic results revealed that GDC-0941 induced the structural change in HSA. Moreover, the conformational change of HSA affected its molecular sizes, as evidenced by AFM. This work provides a useful research strategy for exploring the interaction of GDC-0941 with HSA, thus helping in the understanding of the transport and delivery of dual inhibitors in the blood circulation system.<\/jats:p>","DOI":"10.3390\/molecules27165071","type":"journal-article","created":{"date-parts":[[2022,8,10]],"date-time":"2022-08-10T04:20:32Z","timestamp":1660105232000},"page":"5071","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["PI3K\/mTOR Dual Inhibitor Pictilisib Stably Binds to Site I of Human Serum Albumin as Observed by Computer Simulation, Multispectroscopic, and Microscopic Studies"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2057-4442","authenticated-orcid":false,"given":"Hongqin","family":"Yang","sequence":"first","affiliation":[{"name":"College of Life Sciences, Northwest Normal University, Lanzhou 730070, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7391-2615","authenticated-orcid":false,"given":"Yanjun","family":"Ma","sequence":"additional","affiliation":[{"name":"College of Life Sciences, Northwest Normal University, Lanzhou 730070, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongjie","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Life Sciences, Northwest Normal University, Lanzhou 730070, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junyi","family":"Ma","sequence":"additional","affiliation":[{"name":"College of Life Sciences, Northwest Normal University, Lanzhou 730070, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"L\u00f3pez-Yerena, A., Perez, M., Vallverd\u00fa-Queralt, A., and Escribano-Ferrer, E. (2020). Insights into the Binding of Dietary Phenolic Compounds to Human Serum Albumin and Food-Drug Interactions. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12111123"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.molstruc.2019.01.067","article-title":"Elucidating the binding propensity of naphthyl hydroxamic acid to human serum albumin (HSA): Multi-spectroscopic and molecular modeling approach","volume":"1184","author":"Agrawal","year":"2019","journal-title":"J. Mol. Struct."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1007\/s00044-021-02748-z","article-title":"Albumin roles in developing anticancer compounds","volume":"30","author":"Ribeiro","year":"2021","journal-title":"Med. Chem. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"118298","DOI":"10.1016\/j.saa.2020.118298","article-title":"Physiological changes in the albumin-bound non-esterified free fatty acids critically influence heme\/bilirubin binding properties of the protein: A comparative, in vitro, spectroscopic study using the endogenous biomolecules","volume":"235","author":"Amoorahim","year":"2020","journal-title":"Spectrochim. Acta A Mol. Biomol. Spectrosc."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"114121","DOI":"10.1016\/j.jpba.2021.114121","article-title":"How hydrophilic group affects drug\u2013protein binding modes: Differences in interaction between sirtuins inhibitors Tenovin-1\/Tenovin-6 and human serum albumin","volume":"201","author":"Gan","year":"2021","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"120868","DOI":"10.1016\/j.saa.2022.120868","article-title":"Study on the interaction between 2,6-dihydroxybenzoic acid nicotine salt and human serum albumin by multi-spectroscopy and molecular dynamics simulation","volume":"270","author":"Li","year":"2022","journal-title":"Spectrochim. Acta A Mol. Biomol. Spectrosc."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Ali, M.S., and Al-Lohedan, H.A. (2022). Experimental and Computational Investigation on the Interaction of Anticancer Drug Gemcitabine with Human Plasma Protein: Effect of Copresence of Ibuprofen on the Binding. Molecules, 27.","DOI":"10.3390\/molecules27051635"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"8810","DOI":"10.1039\/C9RA09980H","article-title":"Spectroscopic demonstration of sinapic acid methyl ester complexes with serum albumins","volume":"10","author":"Kasparek","year":"2020","journal-title":"RSC Adv."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Cao, Y., Li, Y., and Zhang, X. (2022). Interactions between Human Serum Albumin and Sulfadimethoxine Determined Using Spectroscopy and Molecular Docking. Molecules, 27.","DOI":"10.3390\/molecules27051526"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"9791","DOI":"10.1039\/C8NJ00655E","article-title":"Interactions between the antiviral drug telaprevir and human serum albumin: A combined study with spectroscopic methods and molecular modeling","volume":"42","author":"Xiong","year":"2018","journal-title":"New J. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"15332","DOI":"10.1039\/D1RA01064F","article-title":"Conformational stability as a quality attribute for the cell therapy raw material human serum albumin","volume":"11","author":"Wynendaele","year":"2021","journal-title":"RSC Adv."},{"key":"ref_12","first-page":"824","article-title":"The characterization of two specific drug binding sites on human serum albumin","volume":"11","author":"Sudlow","year":"1975","journal-title":"Mol. Pharm."},{"key":"ref_13","first-page":"1052","article-title":"Further characterization of specific drug binding sites on human serum albumin","volume":"12","author":"Sudlow","year":"1976","journal-title":"Mol. Pharm."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Mishra, R., Patel, H., Alanazi, S., Kilroy, M., and Garrett, J. (2021). PI3K Inhibitors in Cancer: Clinical Implications and Adverse Effects. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22073464"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Li, H., Prever, L., Hirsch, E., and Gulluni, F. (2021). Targeting PI3K\/AKT\/mTOR Signaling Pathway in Breast Cancer. Cancers, 13.","DOI":"10.3390\/cancers13143517"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Chow, Z., Johnson, J., Chauhan, A., Izumi, T., Cavnar, M., Weiss, H., Townsend, C.M., Anthony, L., Wasilchenko, C., and Melton, M.L. (2021). PI3K\/mTOR Dual Inhibitor PF-04691502 Is a Schedule-Dependent Radiosensitizer for Gastroenteropancreatic Neuroendocrine Tumors. Cells, 10.","DOI":"10.3390\/cells10051261"},{"key":"ref_17","first-page":"503","article-title":"The novel dual PI3K\/mTOR inhibitor GDC-0941 synergizes with the MEK inhibitor U0126 in non-small cell lung cancer cells","volume":"5","author":"Zou","year":"2012","journal-title":"Mol. Med. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"706","DOI":"10.18632\/oncotarget.23091","article-title":"The dual PI3K\/mTOR inhibitor dactolisib elicits anti-tumor activity in vitro and in vivo","volume":"9","author":"Shi","year":"2018","journal-title":"Oncotarget"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"911","DOI":"10.2217\/fon-2020-0035","article-title":"GDC-0941 and CXCL8 (3-72) K11R\/G31P combination therapy confers enhanced efficacy against breast cancer","volume":"16","author":"Li","year":"2020","journal-title":"Future Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.jconrel.2019.12.019","article-title":"Combination of KRAS gene silencing and PI3K inhibition for ovarian cancer treatment","volume":"318","author":"Kim","year":"2020","journal-title":"J. Control. Release"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1167\/iovs.62.12.16","article-title":"Dual Inhibition of Histone Deacetylases and the Mechanistic Target of Rapamycin Promotes Apoptosis in Cell Line Models of Uveal Melanoma","volume":"62","author":"Patel","year":"2021","journal-title":"Invest. Ophth. Vis. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1038\/onc.2012.594","article-title":"The PI3K inhibitor GDC-0941 combines with existing clinical regimens for superior activity in multiple myeloma","volume":"33","author":"Munugalavadla","year":"2014","journal-title":"Oncogene"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1158\/1078-0432.CCR-14-0947","article-title":"First-in-Human Phase I Study of Pictilisib (GDC-0941), a Potent Pan\u2013Class I Phosphatidylinositol-3-Kinase (PI3K) Inhibitor, in Patients with Advanced Solid Tumors","volume":"21","author":"Sarker","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"S197","DOI":"10.1016\/j.ijrobp.2014.05.741","article-title":"The Impact of Hemi-brain Irradiation on Accumulation of PI3K\/mTOR Inhibitors with Limited (GDC-0980) and Robust (GNE-317) Blood-Brain Barrier Penetration","volume":"90","author":"Sio","year":"2014","journal-title":"Int. J. Radiat. Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1110","DOI":"10.1124\/dmd.114.057513","article-title":"Disposition, Distribution of the Phosphatidylinositol 3-Kinase Inhibitors Pictilisib (GDC-0941) and GNE-317 in U87 and GS2 Intracranial Glioblastoma Models--Assessment by Matrix-Assisted Laser Desorption Ionization Imaging","volume":"42","author":"Salphati","year":"2014","journal-title":"Drug Metab. Dispos."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3374","DOI":"10.1158\/1078-0432.CCR-18-3049","article-title":"The Dual PI3K\/mTOR Pathway Inhibitor GDC-0084 Achieves Antitumor Activity in PIK3CA-Mutant Breast Cancer Brain Metastases","volume":"25","author":"Ippen","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1881","DOI":"10.1124\/dmd.116.071423","article-title":"Brain Distribution and Efficacy of the Brain Penetrant PI3K Inhibitor GDC-0084 in Orthotopic Mouse Models of Human Glioblastoma","volume":"44","author":"Salphati","year":"2016","journal-title":"Drug Metab. Dispos."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1785","DOI":"10.1124\/dmd.112.046052","article-title":"Preclinical Assessment of the Absorption and Disposition of the Phosphatidylinositol 3-Kinase\/Mammalian Target of Rapamycin Inhibitor GDC-0980 and Prediction of Its Pharmacokinetics and Efficacy in Human","volume":"40","author":"Salphati","year":"2012","journal-title":"Drug Metab. Dispos."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"6239","DOI":"10.1158\/1078-0432.CCR-12-0720","article-title":"Targeting the PI3K pathway in the brain--efficacy of a PI3K inhibitor optimized to cross the blood-brain barrier","volume":"18","author":"Salphati","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4563","DOI":"10.1021\/acs.molpharmaceut.9b00690","article-title":"Preclinical Evaluation of a Fluorine-18 ((18)F)-Labeled Phosphatidylinositol 3-Kinase Inhibitor for Breast Cancer Imaging","volume":"16","author":"Altine","year":"2019","journal-title":"Mol. Pharm."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"112962","DOI":"10.1016\/j.jpba.2019.112962","article-title":"Interaction of novel Aurora kinase inhibitor MK-0457 with human serum albumin: Insights into the dynamic behavior, binding mechanism, conformation and esterase activity of human serum albumin","volume":"178","author":"Yang","year":"2020","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.etap.2015.12.017","article-title":"Pharmacology, Molecular simulation study of the specific combination between four kinds of phthalic acid esters and human serum albumin","volume":"41","author":"Wu","year":"2016","journal-title":"Environ. Toxicol. Pharm."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.jphotobiol.2018.05.008","article-title":"Characterization of the binding of a novel antitumor drug ibrutinib with human serum albumin: Insights from spectroscopic, calorimetric and docking studies","volume":"184","author":"Tang","year":"2018","journal-title":"J. Photoch. Photobio. B"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"91756","DOI":"10.1039\/C6RA12019A","article-title":"Interaction of an anticancer drug, gefitinib with human serum albumin: Insights from fluorescence spectroscopy and computational modeling analysis","volume":"6","author":"Kabir","year":"2016","journal-title":"RSC Adv."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3096","DOI":"10.1021\/bi00514a017","article-title":"Thermodynamics of protein association reactions: Forces contributing to stability","volume":"20","author":"Ross","year":"1981","journal-title":"Biochemistry"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.foodchem.2018.11.037","article-title":"Insights into protein recognition for \u03b3-lactone essences and the effect of side chains on interaction via microscopic, spectroscopic, and simulative technologies","volume":"278","author":"Sun","year":"2019","journal-title":"Food Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"117330","DOI":"10.1016\/j.saa.2019.117330","article-title":"Probing the interaction of a coumarin-di(2-picolyl)amine hybrid drug-like molecular entity with human serum albumin: Multiple spectroscopic and molecular modeling techniques","volume":"223","author":"Khan","year":"2019","journal-title":"Spectrochim. Acta A Mol. Biomol. Spectrosc."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1021\/acs.molpharmaceut.8b00864","article-title":"In Vitro Cytotoxicity and Interaction of Noscapine with Human Serum Albumin: Effect on Structure and Esterase Activity of HSA","volume":"16","author":"Maurya","year":"2019","journal-title":"Mol. Pharm."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"111581","DOI":"10.1016\/j.molliq.2019.111581","article-title":"Multiple spectroscopic and theoretical investigation of meso-tetra-(4-pyridyl)porphyrin-ruthenium(II) complexes in HSA-binding studies. Effect of Zn(II) in protein binding","volume":"294","author":"Chaves","year":"2019","journal-title":"J. Mol. Liq."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Fu, Y., Wang, J., Wang, Y., and Sun, H. (2022). Investigating the Effect of Tyrosine Kinase Inhibitors on the Interaction between Human Serum Albumin by Atomic Force Microscopy. Biomolecules, 12.","DOI":"10.3390\/biom12060819"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Rimac, H., Tandari\u0107, T., Vianello, R., and Boji\u0107, M. (2020). Indomethacin Increases Quercetin Affinity for Human Serum Albumin: A Combined Experimental and Computational Study and Its Broader Implications. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21165740"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1021\/ci4007326","article-title":"Application of Docking and QM\/MM-GBSA Rescoring to Screen for Novel Myt1 Kinase Inhibitors","volume":"54","author":"Wichapong","year":"2014","journal-title":"J. Chem. Inf. Model."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1093\/glycob\/cww055","article-title":"Computational analysis of interactions in structurally available protein\u2013glycosaminoglycan complexes","volume":"26","author":"Samsonov","year":"2016","journal-title":"Glycobiology"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/16\/5071\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:06:24Z","timestamp":1760141184000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/16\/5071"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,9]]},"references-count":43,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["molecules27165071"],"URL":"https:\/\/doi.org\/10.3390\/molecules27165071","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,9]]}}}