EXPLORING ISO-INDOLINONES AND ARISTOLACTAMS AS POTENTIAL CDK7 INHIBITORS USING CHEMINFORMATICS TOOLS

Abstract

Isoindolin-1-ones are heterocyclic molecules with useful therapeutic properties. Synthetic and medicinal research groups have designed many methodologies for these compounds due to their intriguing biological activity for these compounds. The development of small molecular scaffolds as specific CDK inhibitors is a promising strategy in the discovery of anticancer drugs. In silico evaluation of the isoindolin-1- ones and aristolactam skeleton is done using Cheminformatics tools to evaluate the bioactivity of the virtually synthesized library of 48 compounds. The protein target (CDK7) and ligand 7 had the maximum obtained docking energy of -10.1 kcal/mol, which revealed four hydrogen bonding interactions with the amino acid residues LYS139, ASN141, ASN142, and MET94. The hydrogen bonding interactions in the docked complexes of CDK7 (1UA2.pdb) and active ligands were analysed. Out of 48 ligands, 41 ligands exhibited hydrogen bonding Interactions. With the help of MD simulations, the molecular docking results were further verified. Examining the root mean square deviation, the stability of the simulated complexes was thoroughly tested during the Molecular Dynamics analysis. Our hits exhibit superior qualities to known CDK7 inhibitors, according to the comprehensive pharmacokinetic parameters that were predicted. Both ligands 7 and 14 showed good scores in pKCSM characteristics such as intestinal absorption in humans, P-glycoprotein I and II inhibitors, central nervous system permeability, blood-brain barrier permeability, etc. The results indicate that Isoindolin-1-ones and phenanthrene lactam moieties are showing anti-cancer action because they have remarkable drug-like features and could serve as effective Cyclin-Dependent kinase inhibitors 7 (CDK7).