Computational prediction of 11β-hydroxysteroid dehydrogenase inhibitors from n-butanol fraction of Blighia welwetschii (Hiern) leaf for the management of type-2 diabetes.

Human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) is an enzyme that catalyzes the generation of active cortisol from cortisone, thus regulating the availability of glucocorticoids for the steroid receptor. The involvement of this process in insulin insensitivity has established the catalyst as therapeutic target in type-2 diabetes management. Herein, potent antagonists of 11β-HSD-1 were predicted from bioactive compounds identified from n-butanol fraction of B. welwitschi leaf using chromatography method (HPLC). Molecular docking, MM/GBSA evaluation, autoQSAR modeling, e-pharmacophore modeling, and molecular dynamics simulation of the bioactive compounds were carried out against 11β-HSD-1 employing Schrodinger suite (2017-1). Seven out of the ten bioactive compounds from the fraction showed a higher degree of binding affinity against 11β-HSD-1 compared with the co-crystalized ligand. The post-docking analysis revealed strong interaction due to the hydrogen bond formation between the molecules and amino acid present at the catalytic site of 11β-HSD-1. Rutin showed the highest binding affinity (-13.980 kcal/mol) among the hits comparable to the co-crystalized ligand (-7.576 kcal/mol). The binding free energy (ΔG bind ) evaluation validates the inhibitory potential of the docked complexes, which exclusively confirmed cyaniding-3-o-glucoside (-62.022 kcal/mol) with the highest binding energy followed by rutin (-59.629 kcal/mol). The molecular dynamics simulations predicted the stability of rutin and quercetin-3-o-glycoside complex with 11β-HSD-1 through 100 ns with minimum fluctuation and more H-bond observed between the two top scored 11β-HSD-1-compound complexes compared to the 11β-HSD-1-co-crystalized ligand complex. The pharmacokinetic profile revealed that the hit compounds are promising drug candidates except for rutin which violated more than one Lipinski's rule of five. This study revealed that bioactive compounds identified from B. welwitschi leaves demonstrated good inhibitory potential against 11β-HSD-1. Therefore, these bioactive molecules require experimental validation as 11β-HSD-1 antagonists for type 2 diabetes management.Communicated by Ramaswamy H. Sarma.