Molecular modeling study of pyrrolidine derivatives as novel myeloid cell leukemia-1 inhibitors through combined 3D-QSAR, molecular docking, ADME/Tox and MD simulation techniques.

A series of pyrrolidine derivatives have been used to study the main structural requirements for designing novel Mcl-1 inhibitors. For this purpose, three models CoMSIA, CoMFA and HQSAR were generated using QSAR molecular modeling techniques. The statistical results of the CoMFA ( = 0.689;  = 0.999; = 0.986), CoMSIA ( = 0.614; = 0.923; = 0.815) and HQSAR (= 0.603;  = 0.662;  = 0.743) models showed good stability and predictability. The results of the models were presented as contours and colored fragments indicating the favorable and unfavorable contribution to the inhibitory activity of Mcl-1. Based on the obtained results, four new compounds were designed with more potent predicted pIC inhibitory activity. The ADME/Tox results and the pharmacokinetic properties revealed that these four compounds are orally bioavailable and show good permeability. In addition the four compounds showing non-inhibitors of CYP3A4 and CYP2D6 with the exception of Pred03. At the level of toxicity profile, the compounds Pred01, Pred02 and Pred03 showed interesting results and showed no AMES toxicity, no hERG inhibition and no skin sensitization. Molecular docking results were used to uncover the mode of interaction between the ligand and key residues of protein binding site. Molecular docking results were supported by molecular simulation and binding free energy estimation (MMPBSA). These results demonstrate the stability of the analyzed compounds in the target protein binding site during a 100 ns trajectory. Finally, all these results create a strong lead to develop promising new Pyrrolidine-based inhibitors against Mcl-1.Communicated by Ramaswamy H. Sarma.