Combined QSAR Model and Chemical Similarity Search for Novel HMGCoA Reductase Inhibitors for Coronary Heart Disease

Coronary heart disease generally occurs due to cholesterol accumulation in the walls of the heart arteries. Statins are the most widely used drugs which work by inhibiting the active site of 3-Hydroxy-3-methylglutaryl-CoA reductase (HMGCR) enzyme that is responsible for cholesterol synthesis. A series of atorvastatin analogs with HMGCR inhibition activity have been synthesized experimentally which would be expensive and time-consuming.

In the present study, we employed both the QSAR model and chemical similarity search for identifying novel HMGCR inhibitors for heart-related diseases. To implement this, a 2D QSAR model was developed by correlating the structural properties to their biological activity of a series of atorvastatin analogs reported as HMGCR inhibitors. Then, the chemical similarity search of atorvastatin analogs was performed by using PubChem database search.

The three-descriptor model of charge (GATS1p), connectivity (SCH-7) and distance (VE1_D) of the molecules is obtained for HMGCR inhibition with the statistical values of R2= 0.67, RMSEtr= 0.33, R2 ext= 0.64 and CCCext= 0.76. The 109 novel compounds were obtained by chemical similarity search and the inhibition activities of the compounds were predicted using QSAR model, which were close in the range of experimentally observed threshold.

The present study suggests that the QSAR model and chemical similarity search could be used in combination for identification of novel compounds with activity by in silico with less computation and effort.