Computational design of novel AKT inhibitors

Abstract

The study entails the computational design of novel anticancer compounds which specifically targets the AKT signaling pathway by inhibit the AKT protein. The work was done by carrying out a molecular docking study on nine (9) identified approved FDA drugs collected from the bindingDB.org website. The results of the docking study revealed that A-674563 had the best-free energy of binding value of − 32.63 kcal/mol, while AT-7867 and AZD563 molecules were reported to have − 30.978 and − 27.668 kcal/mol binding energy value, respectively. Molecule A674563 was selected as lead compound further subjected to a structure-based drug design, where a fragment was incorporated or attached to the side chain of the lead and re-docked in the same binding pocket of the AKT receptor target. The results of our findings led to the identification of two novel compounds (molecules 5a and 7a), which were found to better inhibit AKT protein with a binding affinity values of − 36.015 kcal/mol and − 33.324 kcal/mol, respectively. Since their values were significantly better than that of the lead molecule especially when considering their stability in terms of the number of hydrogen bond they formed the amino acids in the AKT-binding pocket.