Design of novel coumarins as potent Mcl-1 inhibitors for cancer treatment guided by 3D-QSAR, molecular docking and molecular dynamics

Myeloid cell leukemia-1 (Mcl-1) is a protein that belongs to a large group of proteins called B cell lymphoma-2 (Bcl-2) which are involved in controlling of apoptosis via interacting with other Bcl-2 family. Various studies showed that Mcl-1 is overexpressed in cancer cells. Thus, it is a promising target for cancer treatment. In the present study, in silico drug design approaches were applied on a library of 33 coumarin derivatives with Mcl-1 inhibitory activity. Firstly, 3D-QSAR study was performed using Gaussian field-based QSAR resulting in a good predictive model with r2 value of 0.80 and q2 value of 0.81 and Pearson-r value of 0.95. Depending on the established model, 10 novel designed compounds were predicted to have more than 10-fold inhibitory activity against Mcl-1 compared to the reference compound. Moreover, these designed molecules have good ADMET properties within the recommended range. Secondly, molecular docking and molecular dynamic simulations were performed to locate the newly designed inhibitors into protein active site to discover how they fit together in the most reliable conformations and address the molecular interactions stability. The in silico methods offer guidance to rational drug design of new compounds with improved potency