Comparative Molecular Field Analysis of Pyrrolopyrimidines as LRRK2 Kinase Inhibitors

Abstract

Leucine rich repeat kinase 2 (LRRK2) is a highly promising target for Parkinson's disease (PD) that affects millions of people worldwide. A three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis was performed on a series of pyrrolopyrimidine-based selective LRRK2 kinase inhibitors. This study was performed to rationalize the structural requirements responsible for the inhibitory activity of these compounds. A reliable 3D-QSAR model was developed using comparative molecular field analysis (CoMFA) technique. The model produced statistically acceptable results with a cross-validated correlation coefficient ($q^2$ 수식 이미지) of 0.539 and a non-cross-validated correlation coefficient ($r^2$ 수식 이미지) of 0.871. Robustness of the model was further evaluated by bootstrapping and progressive scrambling analysis. This work could assist in designing more potent LRRK2 inhibitors.