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

• DOI: 10.1016/j.imu.2021.100765
• Publication Date: 2021-10-19T16:21:41Z
• Authors: Esraa Albasher Osman; Mohammed Abdalrah...; Mohja Omer Abdelr...; Mubarak Fadlalla Ali; Shima Albasher Osman; Yasmin Mohamed Tanir; Mohammed Abdelrahman; Walaa Ibraheem; Abdulrahim A. Alzain
• Keywords: Docking (animal); Drug Design; Rational design

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