MOLECULAR TARGETS AS POTENTIAL PI3Kα INHIBITORS AGAINST AGGRESSIVE METASTATIC DUCTAL AND LOBULAR CARCINOMA
DOI:
https://doi.org/10.22159/ijap.2024v16i5.51514Keywords:
Drug repurposing, TNBC, PI3Kα, Molecular docking and dynamicsAbstract
Objective: This study aimed to identify active compounds among existing molecules by drug repositioning as potential hits of Phosphoinositide 3-Kinase (PI3Kα) inhibitors. FDA-approved ligands were docked using structure-based in silico screening, and the top ten molecules based on docking score were studied for their in silico pharmacokinetic and ligand-receptor interactions.
Methods: FDA-approved ligands were docked with the protein PI3Kα enzyme (PDP ID: 4JPS) and were checked for their molecular interactions and docking scores using the GLIDE program of Schrödinger software. The top 10 ligands were subjected to ADMET and MMGBSA studies to predict pharmacokinetic properties and binding affinity. The best two molecules and the standard alpelisib were subjected to Molecular dynamics with 100 nsec simulation time to deduce interaction at the atomic level.
Results: Two molecules, ZINC000003794794 (Mitoxantrone) and ZINC000004098633 (Polydatin), were found to be promising based on docking score, ligand interaction diagram, and MMGBSA scores of-13.084 and-11.364 and-75.38 and-58.88 respectively and were in a comparable range to the standard alpelisib. These two molecules were then subjected to Induced Fit Docking (IFD) and molecular dynamics to better understand protein stability and inhibitor activity in physiological conditions. The IFD values of these molecules were very close to the standard, and the residues of the best poses coincided with the desired residues, such as V851, S854, and Q859, seen in the alpelisib.
Conclusion: However, further in vitro and in vivo screening is needed to confirm the PI3Kα inhibitory activity of these ligands, which could serve as promising lead molecules in treating TNBC with fewer side effects compared to existing drugs.
Downloads
References
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-74. doi: 10.1016/j.cell.2011.02.013, PMID 21376230.
Arnold M, Morgan E, Rumgay H, Mafra A, Singh D, Laversanne M. Current and future burden of breast cancer: global statistics for 2020 and 2040. Breast. 2022;66:15-23. doi: 10.1016/j.breast.2022.08.010, PMID 36084384.
Dwivedi U, Jain A. Ali Fb, Ali M. Evaluation of serum and salivary Ca-125 in breast cancer patients-an analytical study. Asian J Pharm Clin Res. 2023;16(4):97-9. doi: 10.22159/ajpcr.2023.v16i4.46864.
Sotiriou C, Pusztai L. Geneexpression signatures in breast cancer. N Engl J Med. 2009;360(8):790-8. doi: 10.1056/NEJMra0801289.
De Laurentiis M, Cianniello D, Caputo R, Stanzione B, Arpino G, Cinieri S. Treatment of triple negative breast cancer (TNBC): current options and future perspectives. Cancer Treat Rev. 2010;36Suppl 3:S80-6. doi: 10.1016/S0305-7372(10)70025-6, PMID 21129616.
Zucca Matthes G, Urban C, Vallejo A. Anatomy of the nipple and breast ducts. Gland Surg. 2016;5(1):32-6. doi: 10.3978/j.issn.2227-684X.2015.05.10, PMID 26855906.
Vernieri C, Milano M, Brambilla M, Mennitto A, Maggi C, Cona MS. Resistance mechanisms to anti-HER2 therapies in HER2-positive breast cancer: current knowledge new research directions and therapeutic perspectives. Crit Rev Oncol Hematol. 2019;139:53-66. doi: 10.1016/j.critrevonc.2019.05.001, PMID 31112882.
Costa RL, Han HS, Gradishar WJ. Targeting the PI3K/AKT/mTOR pathway in triple-negative breast cancer: a review. Breast Cancer Res Treat. 2018;169(3):397-406. doi: 10.1007/s10549-018-4697-y, PMID 29417298.
Leevers SJ, Vanhaesebroeck B, Waterfield MD. Signalling through phosphoinositide 3-kinases: the lipids take centre stage. Curr Opin Cell Biol. 1999;11(2):219-25. doi: 10.1016/s0955-0674(99)80029-5, PMID 10209156.
Ali YS, Mahdi MF, Razik BM. In silico evaluation of binding interaction and ADME properties of novel 5-(Thiophen-2-Yl)-1,3,4-oxadiazole-2-amine derivatives as antiproliferative agents. Int J App Pharm. 2023;15(1):141-6. doi: 10.22159/ijap.2023v15i1.46488.
Sabbah DA, Hajjo R, Bardaweel SK, Zhong HA. Phosphatidylinositol 3-kinase (PI3K) inhibitors: a recent update on inhibitor design and clinical trials (2016-2020). Expert Opin Ther Pat. 2021;31(10):877-92. doi: 10.1080/13543776.2021.1924150, PMID 33970742.
Curigliano G, Shah RR. Safety and tolerability of phosphatidylinositol-3-Kinase (PI3K) inhibitors in oncology. Drug Saf. 2019;42(2):247-62. doi: 10.1007/s40264-018-0778-4, PMID 30649751.
Miricescu D, Totan A, Stanescu Spinu II, Badoiu SC, Stefani C, Greabu M. PI3K/AKT/mTOR signaling pathway in breast cancer: from molecular landscape to clinical aspects. Int J Mol Sci. 2020;22(1):1-24. doi: 10.3390/ijms22010173, PMID 33375317.
Hoxhaj G, Manning BD. The PI3K AKT network at the interface of oncogenic signalling and cancer metabolism. Nat Rev Cancer. 2020;20(2):74-88. doi: 10.1038/s41568-019-0216-7, PMID 31686003.
Yang J, Nie J, Ma X, Wei Y, Peng Y, Wei X. Targeting PI3K in cancer: mechanisms and advances in clinical trials 06. J Biol Sci. 2019;18(1):26. doi: 10.1186/s12943-019-0954-x.
Rodon J, Dienstmann R, Serra V, Tabernero J. Development of PI3K inhibitors: lessons learned from early clinical trials. Nat Rev Clin Oncol. 2013;10(3):143-53. doi: 10.1038/nrclinonc.2013.10, PMID 23400000.
Racz A, Mihalovits LM, Bajusz D, Heberger K, Miranda Quintana RA. Molecular dynamics simulations and diversity selection by extended continuous similarity indices. J Chem Inf Model. 2022 Jul 25;62(14):3415-25. doi: 10.1021/acs.jcim.2c00433, PMID 35834424.
Durrant JD, McCammon JA. Molecular dynamics simulations and drug discovery. BMC Biol. 2011;9(1):71. doi: 10.1186/1741-7007-9-71, PMID 22035460.
Yu M, Chen J, Xu Z, Yang B, He Q, Luo P. Development and safety of PI3K inhibitors in cancer. Arch Toxicol. 2023;97(3):635-50. doi: 10.1007/s00204-023-03440-4, PMID 36773078.
Savas P, Lo LL, Luen SJ, Blackley EF, Callahan J, Moodie K. Alpelisib monotherapy for PI3K-altered pretreated advanced breast cancer: a Phase II study. Cancer Discov. 2022;12(9):2058-73. doi: 10.1158/2159-8290.CD-21-1696, PMID 35771551.
Furet P, Guagnano V, Fairhurst RA, Imbach Weese P, Bruce I, Knapp M. Discovery of NVP-BYL719 a potent and selective phosphatidylinositol-3 kinase alpha inhibitor selected for clinical evaluation. Bioorg Med Chem Lett. 2013;23(13):3741-8. doi: 10.1016/j.bmcl.2013.05.007, PMID 23726034.
Sastry GM, Adzhigirey M, Day T, Annabhimoju R, Sherman W. Protein and ligand preparation: parameters protocols and influence on virtual screening enrichments. J Comput Aided Mol Des. 2013;27(3):221-34. doi: 10.1007/s10822-013-9644-8, PMID 23579614.
Jayanthi K, Ahmed SS, Baqi MA, Afzal Azam M. Molecular docking dynamics of selected benzylidene aminophenyl acetamides as TMK inhibitors using high throughput virtual screening (HTVS). Int J App Pharm. 2024;16(3):290-97. doi: 10.22159/ijap.2024v16i3.50023.
Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT. Glide: a new approach for rapid accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem. 2004 Mar;47(7):1739-49. doi: 10.1021/jm0306430, PMID 15027865.
Jain AN. Scoring functions for protein ligand docking. Curr Protein Pept Sci. 2006;7(5):407-20. doi: 10.2174/138920306778559395, PMID 17073693.
Friesner RA, Murphy RB, Repasky MP, Frye LL, Greenwood JR, Halgren TA. Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein ligand complexes. J Med Chem. 2006;49(21):6177-96. doi: 10.1021/jm051256o, PMID 17034125.
Godschalk F, Genheden S, Soderhjelm P, Ryde U. Comparison of MM/GBSA calculations based on explicit and implicit solvent simulations. Phys Chem Chem Phys. 2013;15(20):7731-9. doi: 10.1039/c3cp00116d, PMID 23595060.
Allegra M, Tutone M, Tesoriere L, Attanzio A, Culletta G, Almerico AM. Evaluation of the IKKβ binding of indicaxanthin by induced fit docking binding pose metadynamics and molecular dynamics. Front Pharmacol. 2021;12:701568. doi: 10.3389/fphar.2021.701568, PMID 34566634.
Mishra R, Patel H, Alanazi S, Kilroy MK, Garrett JT. PI3K inhibitors in cancer: clinical implications and adverse effects. Int J Mol Sci. 2021;22(7):3464. doi: 10.3390/ijms22073464, PMID 33801659.
Pascual J, Turner NC. Targeting the PI3-kinase pathway in triple-negative breast cancer. Ann Oncol. 2019;30(7):1051-60. doi: 10.1093/annonc/mdz133, PMID 31050709.
Halder D, Das S, Joseph A, Jeyaprakash RS. Molecular docking and dynamics approach to in silico drug repurposing for inflammatory bowels disease by targeting TNF alpha. J Biomol Struct Dyn. 2023;41(8):3462-75. doi: 10.1080/07391102.2022.2050948, PMID 35285757.
Karami A, Fakhri S, Kooshki L, Khan H. Polydatin: pharmacological mechanisms therapeutic targets biological activities and health benefits. Molecules. 2022;27(19):6474. doi: 10.3390/molecules27196474, PMID 36235012.
Cheng H, Orr ST, Bailey S, Brooun A, Chen P, Deal JG. Structure-based drug design and synthesis of PI3Kα-selective inhibitor (PF-06843195). J Med Chem. 2021;64(1):644-61. doi: 10.1021/acs.jmedchem.0c01652, PMID 33356246.
Hanan EJ, Braun MG, Heald RA, Macleod C, Chan C, Clausen S. Discovery of GDC-0077 (Inavolisib) a highly selective inhibitor and degrader of mutant PI3Kα. J Med Chem. 2022;65(24):16589-621. doi: 10.1021/acs.jmedchem.2c01422, PMID 36455032.
Stein M, Borovik R, Robinson E. Mitoxantrone as second line single agent in metastatic breast cancer. Oncology. 1991;48(4):265-9. doi: 10.1159/000226940, PMID 1891166.
Wang H, Wang Y, Li C, Wang H, Geng X, Hu B. Structural basis for tailor-made selective PI3K α/β inhibitors: a computational perspective. New J Chem. 2021;45(1):373-82. doi: 10.1039/D0NJ04216A.
Bhaskar BV, Rammohan A, Babu TM, Zheng GY, Chen W, Rajendra W. Molecular insight into isoform-specific inhibition of PI3K-α and PKC-η with dietary agents through an ensemble pharmacophore and docking studies. Sci Rep. 2021;11(1):12150. doi: 10.1038/s41598-021-90287-3, PMID 34108504.
Published
How to Cite
Issue
Section
Copyright (c) 2024 ARPITH MATHEW, SUBHAM DAS, LATE ALEX JOSEPH, SUMIT RAOSAHEB BIRANGAL, JANE MATHEW
![Creative Commons License](http://i.creativecommons.org/l/by/4.0/88x31.png)
This work is licensed under a Creative Commons Attribution 4.0 International License.