Computational approaches for evaluation of isobavachin as potential inhibitor against t877a and w741l mutations in prostate cancer

Prostate cancer is the World’s second most common cancer, with the fifth-highest male mortality rate. Point mutations such as T877A and W741L are frequently seen in advanced prostate cancer patients, conferring drug-resistance and hence driving cancer growth. Such occurrence of drug resistance in prostate cancer necessitates designing of suitable ligands to ensure better interactions with the receptors which can block the progression of the disease. The present study focus on the modification of plant-derived flavonoids that might act as inhibitors against such point mutations namely, T877A and W741L. In T877A mutation threonine is substituted by alanine at the 877 codon and W741L mutation, tryptophan is substituted by lysine at the 741 codon in prostate cancer. The study revolved on the aspect of the evaluation of Isobavachin and its derivatives as a potential agent to tackle such point mutations by using the in silico approach. A total of 98 molecular dockings were performed to find the ligand-receptor complexes with the lowest binding energy employing Autodock Software to conduct the blind and site-specific docking. Additionally, ligands were screened for Drug-likeness and toxicity using several tools yielding eight possible drug candidates. Based on the results of Molecular Docking, Drug-likeness, and ADMET testing, ten structures, including six complexes and three receptors were subjected to molecular dynamics simulation of 100 ns covering RMSD, RMSF, Rg, and MM/PBSA. Based on the simulation results, Isobavachin, IsoMod4, and IsoMod7 were concluded to be stable and exhibited potential properties for developing a novel drug to combat prostate cancer and its associated drug-resistance. Communicated by Ramaswamy H. Sarma