Computation of pharmacophore models for the prediction of mitogen-activated protein kinase activated protein kinase-2 inhibitory activity of pyrrolopyridines

摘要

This article is an attempt to formulate the three-dimensional pharmacophore modelling of pyrrolopyridine derivatives inhibiting mitogen-activated protein kinase activated protein kinase-2 (MK_2). To understand the essential structural features for MK_2 inhibitors, pharmacophore hypothesis were built on the basis of a set of known MK_2 inhibitors selected from literature using PHASE program. Three pharmacophore models with one hydrogen-bond acceptor (A), two hydrogen-bond donors (D), one hydrophobic group (H) and one aromatic ring (R) as pharmacophoric features were developed. Amongst them the pharmacophore hypothesis ADDHR1 yielded a statistically significant 3D-QSAR model with 0.926 as R2 value and was considered to be the best pharmacophore hypothesis. The developed pharmacophore model was externally validated by predicting the activity of test set molecules. The squared predictive correlation coefficient of 0.882 was observed between experimental and predicted activity values of test set molecules. The geometry and features of pharmacophore was expected to be useful for the design of selective MK_2 inhibitors.