Rational Computational Study for New Kinase Inhibitors

The development of new drugs can present several problems, it is a important obstacle the ability to adapt a molecule that is a potent pharmacological inhibitor and that is also possible to execute its synthesis. Quinazolines are known to be capable of inhibiting kinases. Thus, a detailed study was carried out to propose new quinazolines with already known synthetic routes, and that were promising for the ability to inhibit kinases. A drug candidate molecule shall be proposed to have a good absorption, an extensive distribution so it’s capable of reaching the desired therapeutic targets. Lipinski's Rule of 5 in computational studies has been applied to select more promising molecules. In this study, the molecules proposed for the synthesis were systematically designed in appropriate computational programs to test several substituents of the quinazoline nucleus on the capacity of these molecules to be considered inhibitors of kinases. Six molecules were selected with the best results to inhibit kinases. In the study to evaluate the variation of substituents, the result obtained for the 8-position of the quinazoline ring and with the -Cl substituent at that ring position presented 60% of the 10 best molecules capable of inhibiting kinases. The molecular docking study confirmed that the two most promising molecules to inhibit kinase also obtained the best results to inhibit AKT kinase. Therefore, through this study it was possible to select six more promising molecules to be synthesized and available in large screening tests for several therapeutic targets known as High-Throughput Screening.