Structure based virtual screening of natural product molecules as glycosidase inhibitors.

Objective of the present investigation comprised of the application of in silico methods to discover novel natural product (NP) based potential inhibitors for carbohydrate mediated diseases. Structure based drug design studies (molecular docking and structure based pharmacophore analysis)  were carried out on a series of natural product compounds to identify significant bioactive molecules to inhibit α-mannosidase (I and II) and β-galactosidase enzymes. Furthermore, protein ligand interaction fingerprint analysis, molecular dynamics simulations and molecular access system (MACCS) fingerprint analysis were performed to understand the binding behaviors of the studied molecules. The results derived from these analyses showed that the identified compounds exhibit significant binding interactions with the active site residues. The compounds, NP-51, NP-81 and NP-165 have shown significant docking score against the studied enzymes (α-mannosidases-I, α-mannosidases-II and β-galactosidases). The fingerprint studies showed that the presence of rings (aromatic or aliphatic) with sulfur atoms, nitrogen atoms, methyl groups, etc. have favorable effects on the α-mannosidase II inhibitory activity. However, the presence of halogen atoms substituted in the molecules have reduced inhibitory ability against α-mannosidase II. The compound, NP-165 has significant activity against both enzymes (α-mannosidases and β-galactosidases). These studies accomplished that the compounds identified through in silico methodologies can be used to develop semisynthetic derivatives of the glycosidase inhibitors and can be screened for the treatment of different carbohydrate mediated diseases. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-021-00115-9.