A potential anticancer dihydropyrimidine derivative and its protein binding mechanism by multispectroscopic, molecular docking and molecular dynamic simulation along with its in-silico toxicity and metabolic profile

Human serum albumin (HSA) is the core protein in the systemic circulation and has a fundamental role in transportation and distribution of ligands in-vivo. In this study, a newly synthesized and patented anticancer dihydropyrimidine derivative; 4-(4-ethoxyphenyl)-5-(3,4,5- trimethoxybenzoyl)-3,4-dihydropyrimidin-2(1H)-one (DHP) was evaluated for its binding to HSA. Ligand-HSA interaction is significant factor to attribute the toxicity or therapeutic potential to a ligand. Multi-spectroscopic studies combined with molecular modelling and molecular dynamic simulation (MDS) were conducted to understand the HSA-DHP binding mechanism. In-silico evaluation of DHP for its toxicity and metabolism was also conducted. Reduction in the binding constants was observed from 6.71 × 104 – 4.5 × 103 at increased temperatures which indicates moderate binding and the interaction was found to follow a static quenching mechanism. Further, Site I on HSA for DHP was established by competition with site specific markers and the results were supported by molecular docking. The stability of the HSA-DHP complex was established with MDS studies. Thermodynamics parameters revealed involvement of hydrogen bonding and van der Waals forces for HSA-DHP binding. An in-silico evaluation of DHP for its toxicity and metabolism provided that the synthesized compound was potentially safe and could be a promising candidate for further studies.