Selective modification of diclofenac to reduce the adverse effects; A computer-aided drug design approach

Diclofenac (DCF) is a non-steroidal anti-inflammatory drug (NSAID), commonly used for the treatment of pain. It can inhibit prostaglandin synthesis by blocking cyclooxygenase (COX). It shows some crucial side effects like gastrointestinal, cardiovascular, renal, and liver injury. The gastrointestinal injury occurred due to the presence of a carboxylic (COOH) group at the core of DCF. The hydroxyl (OH) portion of COOH was replaced by inserting some new functional groups (CH3, OCH3, CH2NH2, NH2, NHCOCH3, NHCONH2, Cl, CF3) considering the retrosynthetic strategy which reduces gastrointestinal side effects with improved chemical and biological activity. Herein, we have investigated the physicochemical, spectral, molecular dynamics, biological and pharmacokinetic properties of the mentioned analogues. Density functional theory (DFT) and time-dependent DFT along with the B3LYP/6-31g (d,p) basis set have been utilized to calculate their geometrical, chemical, and spectral properties. Molecular docking and non-bonding interactions have been performed against human prostaglandin synthase protein (PDB ID: 5F1A) to investigate their binding affinities, modes, and stability. ADMET and PASS prediction studies were performed to investigate their microbial inhibition and toxicological profile. Quantum chemical calculations and spectral characterization support the geometry of newly designed analogues. From the molecular docking simulation, most of the analogues exhibited better binding affinity than the parent drug except for DCF-2. ADMET calculations predict the improved pharmacokinetic and non-carcinogenic properties of all DCF analogues. Biological activities and drug-likeness indicate that all the analogues of DCF have been exposed to comparatively lower action of the gastrointestinal hemorrhage than DCF and exhibit antipyretic, analgesic, and anti-inflammatory actions as well as performed to overcome the poor absorption or permeation of drugs. Finally, based on the above investigation, this study can be helpful to design a potential drug candidate with improved medicinal action and reduced selective adverse effects.