Computational investigation of 4,5-diphenyl-1H-pyrrole-3-carboxylic acid derivatives as B-cell lymphoma-extra large (Bcl-xL) inhibitors by using 3D-QSAR, molecular docking, and molecular dynamics simulations

Abstract

B-cell lymphoma-extra large (Bcl-xL) can inhibit apoptosis via heterodimerization with pro-apoptotic Bcl-2 family proteins, and is over-expressed in many different types of human tumors and has been regarded as a novel cancer therapeutic strategy. Due to the fact that current Bcl-xl inhibitors lack sustained effectiveness and the occurrence of some unpredictable side effects, the development of new inhibitors is necessary. In this study, computational study was applied to a series of Bcl-xL inhibitors to reveal the relationship between structure and activities through applying molecular docking, three-dimensional qualitative structure-activity relationship (3D-QSAR), and molecular dynamic (MD) simulations. A molecular docking study was performed to explore possible modes of action between inhibitors and Bcl-xL protein. Subsequently, 3D-QSAR models were generated with comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). For the best CoMFA model, the Q2 and R2 values were computed as 0.927 and 0.999, while those were computed as 0.943 and 0.998 for the best CoMSIA model. Twenty new Bcl-xL inhibitors were designed, and all their predictive activities were improved than molecules in the dataset based on the contour maps. In addition, MD simulations were conducted to evaluate the stability of the complexes conformed by two inhibitors and Bcl-xL, and the results were consistent with those of the molecular docking and 3D-QSAR studies. Finally, binding free energy was computed through molecular mechanics performed by surface area approach (MM-GBSA), and the result congruent with the activities which indicated van der Waals as well as lipophilic energy contributing the most during the molecular with Bcl-xL protein binding. In brief, our research provided valuable information for further development of Bcl-xL inhibitors.