QSAR, molecular docking and dynamics studies of pyrrolo[2,3-b]pyridine derivatives as bruton's tyrosine kinase inhibitors

Abstract

Bruton's tyrosine kinase (BTK) is involved in multiple signaling pathways regulating the B cell receptor, which is identified as an attractive drug target for lymphoid malignancies. The aims of the present study were to develop a model of Quantitative Structure Activity Relationship (QSAR), and to perform molecular docking and molecular dynamics study of some pyrrolo[2,3-b]pyridine derivatives as potential inhibitor of BTK. The selection and calculation of suitable descriptors was performed by using Molecular Operating Environment (MOE 2009.10), while Multiple Linear Regression (MLR) was used to generate QSAR models. The result of study revealed that the validated QSAR model satisfied the statistical criteria for correlation coefficient, leave-one-out validation coefficient, Fischer's value, and external validation at 0.944, 0.740, 14.873, and 0.792, respectively. Using the validated QSAR model, a novel compound was proposed, which had IC50 lower than that of parent compound. It was then docked into the active site of BTK. The molecular dynamics simulation showed that the new compound was stable during 40 ns dynamics run. The MM-PBSA calculation showed that the new compound had lower binding free energy than those of native ligand and parent compound, which indicated that the new compound could be researched further.