In silico design of diacylglycerol acyltransferase-1 (DGAT1) inhibitors based on SMILES descriptors using Monte-Carlo method

Abstract

ABSTRACTDiabetes, obesity and other diseases related to metabolism are worldwide health problems. These syndromes can be well treated when a particular enzyme-based therapy is developed. Diacylglycerol acyltransferase (DGAT; EC 2.3.1.20) is a microsomal enzyme which is responsible for the synthesis of triglycerides from 1,2-diacylglycerol by catalyzing the acyl-CoA-dependent acylation. The obesity and type-II diabetes can be checked by the inhibition of DGAT1 enzyme. Quantitative structure–activity relationship (QSAR) modelling is an essential technique in drug design and development. To study the aspect of DGAT1 inhibitors, Monte-Carlo method-based QSAR was developed for 197 DGAT1 inhibitors. QSAR models were derived by using the optimal descriptor based on SMILES notation. Different statistical parameters including the novel index of ideality of correlation were applied to validate the generated QSAR models. Four random splits were prepared from the data set. The statistical criteria r2 = 0.8129, CCC = 0.8979 and Q2 = 0.7962 of the validation set of split 1 were the best; therefore, the developed QSAR model of split 1 was decided to be the leading model. The molecular fragments, which were promoter of endpoint increase or decrease were also determined. Thirteen new DGAT1 inhibitors were designed from the lead compound DGAT011.