ABSTRACT:
Acute myeloid leukaemia (AML) is an aggressive hematologic malignancy characterized by uncontrolled proliferation of immature myeloid cells, often leading to poor prognosis and high relapse rates. It remains challenging to treat due to resistance driven by anti-apoptotic proteins BCL-2 and MCL-1, which inhibit apoptosis by stabilizing the mitochondrial membrane. Venetoclax, a BCL-2 inhibitor, faces resistance due to MCL-1 upregulation. This study evaluates five novel inhibitors—AZD5991, BRD-810, BFC1108, VU661013, and A-1210477—that target both BCL-2 and MCL-1 to overcome Venetoclax resistance. Computational tools Molinspiration and SwissADME predicted favourable physicochemical and pharmacokinetic properties for these compounds, with BFC1108 showing the best gastrointestinal absorption. ChemDraw was used for chemical structure representation, and Autodock vina 1.5.7 performed molecular docking with 6QBC (MCL-1) and 6FBX (BCL-2). Docking results showed strong binding affinities of all the compounds and exclusively, with AZD5991 binding to MCL-1 similarly to Venetoclax binding to MCL-1. A-1210477 showed superior binding to BCL-2, suggesting potential as a potent complement. Biovia visualized protein-ligand interactions, supporting dual inhibition of BCL-2 and MCL-1 as an effective strategy to induce apoptosis in AML cells resistant to Venetoclax. In conclusion, AZD5991, BRD-810, BFC1108, VU661013, and A-1210477 are promising dual inhibitors for AML treatment. Computational analysis suggests they may overcome Venetoclax resistance with favourable pharmacokinetic profiles.
Cite this article:
S. Apoorva, Dr. B. Veeresh, G. Harshini, Fatima Mirza.In Silico Studies of Novel BCL-2 and MCL-1 Inhibitors Using Computational Drug Design Tools. IJRPAS, May 2025; 4 (5): 46-60DOI: https://doi.org/https://doi.org/10.71431/IJRPAS.2025.4505
We
acknowledge the help of G. Pulla Reddy College of Pharmacy, Hyderabad, in
providing the required infrastructure and facilities to conduct this in silico
research study. We thank the Department of Pharmacology and the Department of
Pharmaceutical Chemistry for their technical support and guidance during the
work. We further acknowledge the informative feedback and inspiration provided
by S. Apporva, Assistant Professor, Department of Pharmaceutical Chemistry, and
Dr. Veeresh B., Professor and Head, Department of Pharmacology, as our
corresponding authors.
REFERENCES
1)
Yamashita M, Dellorusso PV, Olson OC, Passegué E. Dysregulated haematopoietic stem
cell behaviour in myeloid leukaemogenesis. Nat Rev Cancer. 2020;20(7):365–82.
2)
Orkin SH, Zon LI. Hematopoiesis: an evolving paradigm for stem cell biology.
Cell. 2008;132(4):631–44.
3)
Wilson A, Laurenti E, Oser G, van der Wath RC, Blanco-Bose W, Jaworski M, et
al. Hematopoietic stem cells reversibly switch from dormancy to self-renewal
during homeostasis and repair. Cell. 2008;135(6):1118–29.
4)
Walter MJ, Shen D, Ding L, Shao J, Koboldt DC, Chen K, et al. Clonal
architecture of secondary acute myeloid leukemia. N Engl J Med. 2012;366(12):1090–8.
5)
Vainchenker W, Delhommeau F, Constantinescu SN, Bernard OA. New mutations and
pathogenesis of myeloproliferative neoplasms. Blood. 2011;118(7):1723–35.
6)
Jan M, Snyder TM, Corces-Zimmerman MR, Vyas P, Weissman IL, Quake SR, et al.
Clonal evolution of preleukemic hematopoietic stem cells precedes human acute
myeloid leukemia. Sci Transl Med. 2012;4(149):149ra118.
7)
Welch JS, Ley TJ, Link DC, Miller CA, Larson DE, Koboldt DC, et al. The origin
and evolution of mutations in acute myeloid leukemia. Cell. 2012;150(2):264–78.
8)
Bose P, Grant S. Mcl-1 as a therapeutic target in acute myelogenous leukemia
(AML). Leuk Res Rep. 2013;2(1) 12–14
9) Dhakal P, Bates M, Tomasson MH, Sutamtewagul
G, Dupuy A, Bhatt VR. Acute myeloid leukemia resistant to Venetoclax-based
therapy: What does the future hold? Blood Rev. 2023;59:101036.
10)
Ramsey HE, Fischer MA, Lee T, Gorska AE, Arrate MP, Fuller L, et al. A Novel
MCL1 Inhibitor Combined with Venetoclax rescues Venetoclax-Resistant Acute
Myelogenous Leukemia. Cancer Discov. 2018;8(12):1566-81.
11)
Hird AW, Tron AE. Recent advances in the development of Mcl-1 inhibitors for
cancer therapy. Pharmacol Ther. 2019;198:59–67
12)
Wei Y, Zhao M. Targeting Bcl-2 Proteins in Acute Myeloid Leukemia. Front Oncol.
2020; 10:584974.
13)
Mabkhot YN, Alatibi F, El-Sayed NNE, Al-Showiman S, Barakat A, Al-Obaid AM, et
al. Antimicrobial activity of some novel armed thiophene derivatives and
PETRA/OSIRIS/Molinspiration (POM) analyses. Molecules. 2016;21(2):222.
14)
Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate
pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small
molecules. Sci Rep. 2017;7:42717.
15) Dmitry A Filimonov , Anastassia V Rudik , Alexander V Dmitriev , Vladimir V Poroikov.
Computer-aided estimation of biological activity profiles of drug substances.
Biomed Res Ther. 2020;7(10):4029–40.
16) Stephen K Burley , Helen M Berman, Jose M Duarte, Zukang Feng, Justin W Flatt, Brian P Hudson,
et al. Protein Data Bank: a comprehensive review of 3D structure data
resources. Nucleic Acids Res. 2023;51(D1): D488–D508.
17)
Rizvi SM, Shakil S, Haneef M. A simple click by click protocol to perform
docking: AutoDock 4.2 made easy for non-bioinformaticians. EXCLI J.
2013;12:831–57.