Molecular modelling studies in explaining the higher GPVI antagonistic activity of the racemic 2-(4-methoxyphenylsulfonyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxamide than its enantiomers

The GPVI receptor on the platelets plays a major role in inhibiting arterial thrombosis with limited risk of bleeding and is considered a potential anti-thrombotic target for arterial thrombosis. In the reported anti-thrombotics, tetrahydropyridoindoles, the title compound was the best inhibitor of the collagen mediated platelet aggregation by antagonizing the platelet receptor GPVI. Interestingly, the racemic title compound showed better antagonism (IC50 racemate = 6.7 μM) than either of its enantiomers (IC50 S enantiomer = 25.3 μM; IC50 R enantiomer = 126.3 μM). In order to explain this, the molecular modelling approaches viz. site map analysis, protein–protein docking and molecular dynamics simulation were carried out, which led to the identification of a second binding site located near the primary antagonist binding site known to bind losartan. The induced fit docking studies for both the enantiomers at the primary and secondary binding sites showed that the S-enantiomer has better interactions at the primary binding site than the R-enantiomer, while the R-enantiomer has better interactions at the secondary site than the S-enantiomer. Hence, the overall interactions of the racemic compound containing equimolar mixture may be higher than any one of the enantiomers and may explain the higher activity than its enantiomers of the racemic compound.