Innovative Design and Assessment of Dual‐targeted c‐Met/PARP1 Inhibitors Using Pyridine‐2‐amine Bioisosteres: Scaffold Hopping, Machine Learning, Molecular Docking, Molecular Dynamics, and ADME/T Analysis

Abstract

Developing new strategies is essential to overcome the growing resistance to PARP1 and c‐Met inhibitors; dual‐targeted compounds offer promising therapeutic potential. Scaffold hopping is used to create inhibitors targeting both c‐Met and PARP1. The active functional groups of crizotinib and olaparib are utilized while incorporating pyridine‐2‐amine bioisosteres as the cores. The designed compounds are screened against the binding sites of the targets, and machine learning (ML) models are then developed to evaluate the screened molecules. The final molecules are subsequently assessed through ADME/T analysis, molecular dynamics (MD) simulations, and binding free energy calculation. ≈500 newly designed inhibitors are generated, among which six compounds are recognized as hit compounds based on their binding affinity to c‐Met and PARP1. The activity of the compounds is assessed against c‐Met and PARP1 using ML, leading to the selection of optimized‐compound 2 (OC2) ((R)‐1‐(2,6‐dichloro‐3‐fluorophenyl)ethyl((2‐amino‐3‐((S)‐aminofluoromethoxy)‐5‐((3‐carbamoyl‐4‐fluorophenyl)amino)pyridin‐4‐yl)methyl)(methyl)carbamate) and OC3 (2‐amino‐6‐methyl‐3‐(((4‐oxo‐3,4‐dihydrophthalazin‐1‐yl)oxy)methyl)‐1‐((1‐(piperidin‐1‐ium‐4‐yl)‐1H‐pyrazol‐4‐yl)methyl)pyridin‐1‐ium) as the most promising candidates for subsequent evaluation through ADME/T analysis. Based on the results, OC2 and OC3 are the promising drug candidates because they can be dual‐targeted inhibitors for c‐Met and PARP1 by specifically targeting vital residues in their binding sites. Further research is necessary for these compounds using both in vitro and in vivo methods.