Design of new 3, 5-disubstituted indole as hematological anticancer agents using 3D-QSAR, molecular docking and drug-likeness studies

Abstract The World Health Organization (WHO) considers cancer as the deadliest disease, due to the increase in death in the 21 century. In the search for new therapeutic molecules, the scientific researches consider the proviral integration moloney (Pim) kinases as promising therapeutic targets for the treatment of hematological cancers. A series of thirty-four 3,5-disubstituted indole derivatives as potent Pim1 kinase inhibitors were studied using 3D-QSAR (CoMFA and CoMSIA) and molecular docking. CoMFA analysis showed Q2 value of 0.56, R2 value of 0.86 and rtest2 value of 0.78, while CoMSIA analysis showed a Q2 value of 0.73, R2 value of 0.93 and rtest2 value of 0.80. The models were generated using 28 compounds as training set and 6 compounds as test set. Furthermore, the contour maps acquired from the CoMSIA and CoMFA models were used to rationalize the principal structural requirement responsible for the activity. As results, four new compounds were designed in silico. Furthermore, the newly designed compound X1 and the most active compound 28 were subjected to molecular docking study in order to validate their stability. Molecule docking shows that compound X1 has greater stability than compound 28. The newly compounds were evaluated for in silico toxicity properties and verified the five Lipinski rules for wet-lab applicability.