Interactions of selected indole derivatives with COX-2 and their in silico structure modifications towards the development of novel NSAIDs

Abstract

Cyclooxygenase-2 (COX-2) is an important enzyme responsible for the formation of potent inflammatory mediators like prostaglandins, prostacyclin and thromboxane. Hence, inhibition of COX-2 is one of the best ways to control the inflammation. Non-steroidal anti-inflammatory drugs can control inflammation by inhibiting Cyclooxygenase. Selective inhibition of COX-2 is preferable over the inhibition of COX-1 because of the fewer adverse effects produced. Molecular modeling and docking of 134 selected indole compounds were done against COX-2. The pharmacophore-based in silico structural modifications of the best scored compounds were carried out in order to enhance the binding affinity and selectivity. The modification resulted in derivatives with better binding energies than that of known COX-2 inhibitors. The four best derivatives in terms of the binding energies were selected and their binding stabilities were studied by molecular dynamics simulation methods.

Keywords:

• COX
• enzyme inhibitors
• structure-based lead design
• molecular modeling
• induced fit docking

Acknowledgment

The authors gratefully acknowledge the ‘Bioinformatics Infrastructure Facility’ (supported by DBT, Govt. of India) located at the Department of Biotechnology and Microbiology, Kannur University for providing the computational work. K.V.D. and C.R. thank Indian Council of Medical Research, New Delhi, for the financial support in the form of Senior Research Fellowships.