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

Abstract

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, R_g, 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

Keywords:

• Omapatrilat
• prodrug
• molecular dynamics simulation
• MM/GBSA
• homology modeling
• QM/MM
• brain carboxylesterase
• stereoisomers

Acknowledgements

We would like to express our sincere gratitude to Professor Fabio Polticelli from the Department of Sciences, University Roma Tre for his valuable guidance.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The datasets supporting the results and conclusion of this manuscript are included within the article and its Supplementary Information files.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.