DESIGN, MOLECULAR MODELING, SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF NEW NSAIDS DERIVATIVES WITH POSSIBLE COX-2 SELECTIVITY

Abstract

ABSTRACT

Background: Effective treatment strategies are required to address the numerous health issues brought on by inflammation. A famous group of drugs used to treat inflammations includes nonsteroidal anti-inflammatory drugs (NSAIDs). Additionally, their indiscriminate inhibition of cyclooxygenase (COX) leads to many undesirable outcomes. The use of selective COX-2 inhibitors has shown promise in reduction of these hazards without sacrificing therapeutic efficacy.

Aim: Creating, synthesizing and evaluating new NSAID compounds that may be COX-2 selective was the objective of this paper. Predicting their binding affinities and modes of interaction with COX-2 enzyme as well as the use of molecular modeling to predict these with synthesized derivatives.

Methods: The synthesis of amide derivatives was done by combining cysteine, aspartic acid and tyrosine with the already-approved NSAID such as diclofenac, mefenamic acid and indomethacin. The structures of these derivatives were characterized after their synthesis through formation of amide bonds via spectroscopic methods. In molecular modelling research carried out, molecules were docked using the Molecular Operating Environment (MOE) program to assess ligand-receptor interaction.

Results: Binding affinities of synthesized NSAID derivatives differed. Through docking studies, this was evident in compound 2 having the highest S score (-8.40), which meant a remarkable COX-2 enzyme binding. The compound with the lowest RMSD value (1.36) was compound 6 which indicated a favorable binding geometry. Particular interactions between amino acids were found which emphasized hydrogen bonding with important residues like Leu 517 and Arg 106.

 A comparison of the synthesized compounds with the well-known COX-2 inhibitors celecoxib and diclofenac revealed possible therapeutic benefits.

Conclusion: The developed NSAID compounds exhibited encouraging COX-2 binding affinities and interaction patterns and pointing to possible COX-2 selectivity. To evaluate these compounds' potential therapeutic uses, more research is needed to determine their pharmacokinetic profiles and in vitro and in vivo anti-inflammatory properties.