In-silico Investigation of Potential Inhibitors of 11-β-Hydroxysteroid Dehydrogenase

Abstract

Diabetes mellitus is a chronic disease plagued with insufficient insulin production or insulin resistance. New targets and disease pathways are emerging and one such is the 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) which catalyses the intracellular conversion of inert cortisone to physiologically active cortisol, functioning to enhance local cortisol action beyond what would be predicted based on simple plasma exposures. This study aimed at exploring the anti-diabetic potential of the bioactive compounds found in Carica papaya. In this study, 59 natural compounds were obtained from literature are used for molecular docking simulations against the 11β-HSD1 receptor target using the Python Prescription (PyRx) 0.8 software. An arbitrary docking score ≤ -8.0 kcal/mol was chosen as the cut-off value. Further screening for drug-likeness, Absorption Distribution Metabolism Excretion and Toxicity (ADMET) properties, Pan Assay Interference Compounds (PAINS), and bioactivity were performed. The compounds were compared to the 11β-HSD1 inhibitor, MK-0916 which was the reference compound and docked against the target with a binding affinity of -8.8 kcal/mol. After docking, 11 compounds emerged with docking of ≤-8.0 kcal/mol, the highest at -8.1 kcal/mol and lowest at -10.7 kcal/mol. The compounds were further screened using Ghose and Verber rule resulting in four compounds i.e. Ibogamine, Clausamine G, Dasycarpidan-1-methanol, acetate (ester) and Phenol-2-methyl-5- (1,2,2- trimethylcyclopentyl). Pharmacokinetic screening (ADMET and bioactivity) was carried out on the four compounds and it was discovered that they have a level of potency but Ibogamine has higher potency of exerting inhibitory function on 11β-HSD1 compared to the control.