Design of prodrug for stereoisomers of omapatrilat to cross the blood-brain barrier using docking, homology modeling, MD, and QM/MM methods

In this study, we designed a suitable ester prodrug for omapatrilat to penetrate the blood-brain barrier and treat CNS diseases. Based on the ADMET properties, the methyl carboxylate ester of omapatrilat was chosen from among several prodrug structures. Sixteen methyl carboxylate esters were constructed for omapatrilat. The structure of brain carboxylesterase was derived via homology modeling, and molecular docking was used to determine the most potent stereoisomers against brain carboxylesterase. The top three stereoisomer complexes, and the apo form of the protein, were then considered using molecular dynamics simulation and MM/GBSA analysis. Following the simulation, structural analysis was performed using RMSD, RMSF, Rg, and hydrogen bond analysis tools. Our data demonstrated that the prodrug of RSSR is a suitable structure for crossing the blood-brain barrier and binding to brain carboxylesterase. In addition, we found via QM/MM calculation that the catalytic reaction of the prodrug of RSSR against brain carboxylesterase occurs via two steps, including acylation and diacylation steps. Based on our findings, we propose a clinical trial of a methyl carboxylate ester prodrug of omapatrilat's RSSR for the treatment of brain diseases.Communicated by Ramaswamy H. Sarma

Automated summary

In this study, we designed a suitable ester prodrug of omapatrilat for CNS diseases by considering its ability to penetrate the blood-brain barrier. The most potent stereoisomers against brain carboxylesterase were determined through molecular docking and homology modeling. Molecular dynamics simulation and structural analysis were performed to confirm the suitability of the prodrug structure for crossing the blood-brain barrier and binding to brain carboxylesterase. Additionally, the QM/MM calculation revealed the catalytic reaction mechanism of the prodrug against brain carboxylesterase.