Synthesis, docking studies, and in silico ADMET predictions of some new derivatives of pyrimidine as potential KSP inhibitors

Abstract

The guanidine functionality has been found in numerous biologically active natural products and several drugs. We have, therefore, directed some of our efforts to synthesize analogs of 2-aminopyrimidine, a guanidine-containing six-membered heterocyclic scaffold, using microwave irradiation. The synthesized compounds have shown structural similarity to ispinesib, a quinazolinone-based KSP inhibitor that has already entered clinical trials. Molecular docking study was carried out to understand the binding modes of these newly synthesized compounds. The results of docking studies showed that these compounds interact with the same active site residues like ispinesib. From the molecular docking study, it was confirmed that these compound might be act as a potential candidate for KSP inhibition. Further lead optimization of drug-like properties was evaluated through in silico predictions by ADMET predictor™ software. The blood brain barrier penetration for both the synthesized compounds is predicted to be high compared to ispinesib. Hence, it is predicted that these compounds have tendency to treat the glioblastoma-like brain cancers. Hence a combination of in silico ADMET studies and molecular docking can help to improve prediction success and these compounds might be act as a potential candidate for KSP inhibition.