A multitier virtual screening study of phytoconstituents as Myeloid Cell Leukemias 1 inhibitors

Myeloid Cell Leukemia 1 (MCL1) is an anti-apoptotic protein that plays a critical role in regulating cell survival, particularly in cancer cells. It is a member of the BCL-2 family of proteins, which control the intrinsic pathway of apoptosis. MCL1 has emerged as a promising target for cancer therapy because it is overexpressed in a wide range of cancers, including breast, lung, prostate, and hematologic malignancies. Due to its remarkable role in cancer progression, it has been reflected as a promising drug target for cancer therapy. A few MCL1 inhibitors have been identified previously, but further research is needed to develop novel, effective and safe MCL1 inhibitors that can overcome resistance mechanisms and minimize toxicity in normal cells. In this study, we aim to search for compounds that target the critical binding site of MCL1 from phytoconstituent library from the IMPPAT database. To accomplish this, a multitier virtual screening approach involving molecular docking and molecular dynamics simulations (MDS) were used to evaluate their suitability for the receptor. Notably, certain screened phytoconstituents have appreciable docking scores and stable interactions toward the binding pocket of MCL1. The screened compounds underwent ADMET and bioactivity analysis to establish their anticancer properties. One phytoconstituent, Isopongaflavone, was identified that exhibiting higher docking and drug-likeness than the already reported MCL1 inhibitor, Tapotoclax. Isopongaflavone and and Tapotoclax, along with MCL1, were subjected to 100 nanoseconds (ns) MDS study to verify their stability inside the binding site of MCL1. The MDS findings demonstrated a strong binding affinity between Isopongaflavone and the MCL1 binding pocket, resulting in reduced conformational fluctuations. This investigation proposes Isopongaflavone as a promising candidate for the development of innovative anticancer therapeutics, pending the necessary validation procedures. Also, the findings provide valuable information for designing MCL1 inhibitors based on the protein's structure.Communicated by Ramaswamy H. Sarma.