Docking Studies On Antidiabetic And Antioxidant Activities Of Pyrazole Derivatives

Abstract

Type 2 diabetes mellitus (T2DM) is a very common metabolic complication that remains challenging to treat effectively with nearly 537 million adults suffering all over the world today with the number expected to be at 783 million by the year 2045. Oxidative stress is central to the pathogenesis of T2DM and it is caused by an imbalance between the production of reactive oxygen species (ROS) and the antioxidant defenses systems of the body. The imbalance accompanies the major features of T2DM such as dysfunction of the beta-cell, insulin resistance, and macro- and microvascular complications. Designing of bifunctional molecules which target the antidiabetic and antioxidant effects should therefore present a promising therapeutic measure of management of T2DM. The pyrazole, a heterocyclic five-membered nitrogen molecule, has become a drug discovery scaffold of interest due to its versatility as a bioisostere, metabolic stability and its capacity to bind multiple enzymatic targets. Recent research on the use of pyrazole derivatives as dual-target agents in the treatment of T2DM has focused on the combinatory use of antidiabetic and antioxidant properties of these compounds. Here, the current study presents findings of the molecular (docking) studies of the eight pyrazole derivatives (P-1 to P-8) with three pharmacologically validated targets: α-glucosidase (PDB: 5NN8), protein tyrosine phosphatase 1B (PTP1B, PDB: 2HNP), and Kelch-like ECH-associated protein 1 AutoDock Vina 1.2.3 was used to conduct docking simulations and GROMACS 2023 was used to validate the simulations. The compound that exhibited the greatest binding affinity was P-5 (ethyl 1-(4-methylphenyl)-3-(4-nitrophenyl)-1H-pyrazole-5-carboxylate) with an energy of -10.67, -10.08, and -8.87 kcal/mol with α-glucosidase, PTP1B and Ke Such binding energies were quite similar to those of reference drugs that include acarbose, ursolic acid, and quercetin. Also, computation of ADMET with SwissADME and pkCSM was used to ensure the drug-likeness of these compounds and fit the Rule of Five and point to high predicted oral bioavailability. These results indicate the possible relevance of pyrazole derivatives as effective dual-target agents in treating T2DM.