In silico study to recognize novel angiotensin-converting-enzyme-I inhibitors by 2D-QSAR and constraint-based molecular simulations

Cardiovascular diseases (CVD) such as heart failure, stroke, and hypertension affect 64.3 million people worldwide and are responsible for 30% of all deaths. Primary inhibition of the angiotensin-converting enzyme (ACE) is significant in the management of CVD. In the present study, the genetic algorithm-multiple linear regressions (GA-MLR) method is used to generate highly predictive and statistically significant (R² = 0.70–0.75, Q²_LOO=0.67–0.73, Q²_LMO=0.66–0.72, CCC_ex=0.70–0.78) quantitative structure-activity relationships (QSAR) models conferring to OECD requirements using a dataset of 255 structurally diverse and experimentally validated ACE inhibitors. The models contain simply illustratable Padel, Estate, and PyDescriptors that correlate structural scaffold requisite for ACE inhibition. Also, constraint-based molecular docking reveals an interaction profile between ligands and enzymes which is then correlated with the essential structural features associated with the QSAR models. The QSAR-based virtual screening was utilized to find novel lead molecules from a designed database of 102 thiadiazole derivatives. The Applicability domain (AD), Molecular Docking, Molecular dynamics, and ADMET analysis suggest two compound D24 and D40 are inflexibly linked to the protein binding site and follows drug-likeness properties.

Communicated by Ramaswamy H. Sarma