Towards to potential 2-cyano-pyrimidines cathepsin-K inhibitors: An in silico design and screening research based on comprehensive application of quantitative structure–activity relationships, molecular docking and ADMET prediction

Abstract

Cathepsin K (CK) is the only cathepsin showing high expression in osteoclasts. CK is considered to be a drug target in treatment of osteoporosis, rheumatoid arthritis and osteoarthritis. Comprehensive application of quantitative structure–activity relationships (QSAR), molecular docking and absorption, distribution, metabolism, excretion and toxicity (ADMET) prediction was conducted for designing and screening for potential CK inhibitors based on 2-cyano-pyrimidine analogs. For the two-dimensional (2D)-QSAR study, a statistical model of PLS_FCFP was chosen for its best evaluated regression statistic values (r2 = 0.759, q2 = 0.637 and r2pred = 0.699). An equation that implied positive or negative contributions for several molecular descriptors was acquired. For the 3D-QSAR study, based on two methods of generation of molecular poses, three fingerprint-based cluster partitions, and two common substructures, 336 candidate CoMFA and CoMSIA models were generated for evaluation of statistic values. Among them, database Minimize_MDL_subs01 provided superior evaluated models: CoMFA model #41 (r2 = 0.994, q2 = 0.746 and r2pred = 0.8693) and CoMSIA model #42 (r2 = 0.983, q2 = 0.753 and r2pred = 0.8676). Informative clues for molecular design were derived from the created QSAR models and, based on them, an in-house library containing 190 purposefully designed unknown compounds was built for screening for potential CK inhibitors. Based on a combination of activity prediction and calculation of binding affinity, unknown compound X139 emerged. Detailed molecular docking studies assisted in unveiling of the interactions between unknown compounds and the target protein. The strong π–π conjugation and preferably formed hydrogen bonds provided evidence that compound X139 had higher predicted activity. The subsequent study of ADMET prediction suggested acceptable drug-like properties for compound X139.