In silico Comparative Study of the Anti-Cancer Potential of Inhibitors of Glucose-6-Phosphate Dehydrogenase Enzyme Using ADMET Analysis, Molecular Docking, and Molecular Dynamic Simulation

Abstract

Cancer is marked by the rapid, unregulated growth and division of abnormal cells, often overwhelming healthy cells and compromising normal function. Given the limitations of current therapies, there is an urgent demand for novel drugs. The enzyme glucose-6-phosphate dehydrogenase (G6PD), essential to the pentose phosphate pathway (PPP) and frequently associated with cancer cell metabolism, presents a promising target for cancer treatment. However, no G6PD inhibitor is yet validated as an approved drug. This study focuses on the in silico assessment and comparative analysis of the anticancer potential of five G6PD inhibitors: glucose-6-phosphate dehydrogenase inhibitor 1 (G6PDi1), 3alpha,21-Dihydroxy-5alpha-pregnant-20-one (THDOC), dehydroepiandrosterone (DHEA), 6-aminonicotinamide (6-AN), and polydatin (PD). Molecular docking results show that G6PDi1 exhibits the highest binding affinity (−8.65 kcal mol⁻¹) among the inhibitors tested. ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) pharmacokinetics, and biological activity assessments identified PD, THDOC, and G6PDi1 as the most promising G6PD inhibitors. Furthermore, a 100 ns molecular dynamics (MD) simulation combined with Molecular Mechanics/Poisson-Boltzmann surface (MM-PBSA) post-simulation analysis indicated stability and compactness for all compounds, with no significant deviations observed throughout the simulation period. These findings suggest THDOC and G6PDi1 as potential candidates for developing effective cancer therapeutics targeting G6PD.