Dihydropyrimidinones as Potential Direct Renin Inhibitors: In Silico Molecular Docking and Molecular Dynamics Approach

Abstract

This study contributes to ongoing efforts to address the global health challenge of hypertension by in silico exploring new inhibitors of the renin-angiotensin-aldosterone system (RAAS). Renin, a key enzyme regulator in this pathway, was selected as the molecular target for treatment intervention. Specifically, the potential of dihydropyrimidinone (DHPM) derivatives as direct renin inhibitors was investigated using the enzyme’s crystal structure (PDB ID: 2V0Z. A total of 440 compounds with substitutions at N1, N3, and C4 of the DHPM core were evaluated through molecular docking. Top-scoring ligands for each substitution type were further assessed through molecular dynamics simulations. Pharmacokinetic properties, including absorption, distribution, metabolism, and excretion (ADME), were predicted using SwissADME, while toxicity risks were assessed with OSIRIS Property Explorer. Compounds 30j and 33h emerged as promising candidates, showing strong binding affinities and favorable pharmacokinetic profiles. Molecular dynamics confirmed the stability of these compounds within the renin complex throughout the simulation period. These results support the potential of DHPM derivatives as lead compounds for the development of new renin-targeted antihypertensive therapies.