| Summary: | Human serum paraoxonase-1 (PON1) is an important hydrolase-type enzyme found in numerous tissues. Notably, it can exist in two isozyme-forms, Q and R, that exhibit different activities. This study presents an in silico (QSAR, Docking, MD and QM/MM) study of a set of compounds on the activity towards the PON1 isoenzymes (QPON1 and RPON1). Different rates of reaction for the Q and R isoenzymes were analyzed by modelling the effect of Q192R mutation on active sites. It was concluded that the Q192R mutation is not even close to the active site, while it is still changing the geometry of it. Using the combined genetic algorithm with multiple linear regression (GA-MLR) technique, several QSAR models were developed and relative activity rates of the isozymes of PON1 explained. From these, two QSAR models were selected, one each for the QPON1 and RPON1. Best selected models are four-variable MLR models for both Q and R isozymes with squared correlation coefficient R<sup>2</sup> values of 0.87 and 0.83, respectively. In addition, the applicability domain of the models was analyzed based on the Williams plot. The results were discussed in the light of the main factors that influence the hydrolysis activity of the PON1 isozymes.
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