Ligand-based Virtual Screening, Consensus Molecular Docking, Multi-target Analysis and Comprehensive ADMET Profiling and MD Stimulation to Find Out Noteworthy Tyrosine Kinase Inhibitor with Better Efficacy and Accuracy

Abstract

Inhibition of BCR–ABL tyrosine kinase plays a crucial role in the management of chronic myelogenous leukemia (CML). The suppression of CML is getting harder because of a distinct pattern of resistance. Developing new types of ABL tyrosine kinase inhibitors along with ABL2, CSF1R, KIT, LCK, PDGFRA, and PDGFRB inhibitors is the main objective of this study that may overcome the drug resistance issue. The current study has been conducted using a kinase database containing 177,000 bioactive molecules, the top 135 molecules were selected with the best docking score and subjected to comprehensive ADMET profiling, multi-target analysis. Based on consensus molecular docking score (AutoDock, Chimera, Achilles, and Mcule), 22 molecules have been screened out which later undertaken for ADME/T profiling. After profiling of ADME/T data, selected molecules subjected to docking with multiple targets. Finally, molecular dynamics simulations had performed to screen the binding accuracy of the four lead molecules with ABL1. MD simulations of the desired complex (ABL1, ABL2, CSF1R, KIT, LCK, PDGFRA, and PDGFRB, among them ABL1 was the prime target) performed and found that PCID 10181160 and PCID 72724706 are the most promising inhibitors comparing to imatinib. These lead molecules are the potential CML inhibitors that could resolve the resistance pattern. Further chemical synthesis, wet lab analysis, and experimental validation deserve the utmost attention.