Structure-based design of new diclofenac: Physicochemical, spectral, molecular docking, dynamics simulation and ADMET studies

Abstract

Diclofenac, a nonsteroidal anti-inflammatory drug, is commonly prescribed for the analgesic, antipyretic and anti-inflammation treatment. It is effectively used in acute and chronic pain. It inhibits the prostaglandin synthesis by blocking cyclooxygenase (COX). However, it shows some crucial side effects like renal, gastrointestinal and cardiovascular injury to the human and other living things. It also causes gastrointestinal side effects like bleeding and perforation if taken at higher dose for a long period of time. Liver toxicity is also another issue related to oral diclofenac. To improve its safety profile, an attempt has been taken to design some new potential drug to reduce the side effects with better medicinal action. The insertion of new functional groups such as CH3, OCH3, F, CF3, OCF3, Cl, OH, COOH, NH2, CH2NH2, CONH2, NHCOCH3 at the different positions of its core structure significantly enhance the chemical and biological performance. Chemical, physical and spectral calculation has been performed by geometry optimization to characterize the newly designed structures. Molecular docking and dynamics simulation have been performed against human prostaglandin synthase protein (PDB ID: 5F19) to predict binding affinity, bonding interaction and stability of protein-drug complex. ADMET predictions have been studied to search for their pharmacokinetic properties like absorption, metabolism and toxicity. Physicochemical and spectral data support the new structural conformation. Molecular docking and dynamics studies disclose improved medicinal effect and pharmacokinetic prediction suggest their reduced side effects and non-carcinogenic properties than the parent drug which lead to develop the novel drug with improved clinical safety.