Virtual screening and QSAR study of some pyrrolidine derivatives as alpha-mannosidase inhibitors for binding feature analysis

• Type: Article in International Scientific Journal
• Date: 2012

Authors

Moorthy, NSHN (Author) Other; Natercia F Bras (Author) FCUP; Maria J Ramos (Author) FCUP; Pedro A Fernandes (Author) FCUP

Journal

Title: Bioorganic and Medicinal Chemistry

Vol. 20

Pages: 6945-6959

ISSN: 0968-0896

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 7 Citations

Scopus - 8 Citations

Scientific classification

FOS: Natural sciences > Chemical sciences

Other information

Authenticus ID: P-002-2C0

DOI: 10.1016/j.bmc.2012.10.011

Abstract (EN): Virtual screening and QSAR analysis were carried out to investigate the binding features of (2R, 3R, 4S)-2-aminomethylpyrrolidine 3,4-diol and the functionalized pyrrolidine derivatives to the alpha-mannosidase I and II enzymes. The QSAR models (possessed considerable R-2, Q(2) values, etc.) suggested that the presence of polar property on the vdW surface (vsurf_W, vsurf_Wp, etc.) of the molecules is important along with the presence of aromatic rings (opr_violation) in the molecules (which also provide hydrophobicity to the molecules). The docking study performed on alpha-mannosidase I and II enzymes pointed that the main interactions occur by hydrogen bonds, hydrophobic pi-pi stacking contacts and salt bridges with the cation calcium (for alpha-mannosidase I) and close interaction with zinc ion (alpha-mannosidase II), respectively. The bond flexibility orientates the aromatic ring in the molecules toward the hydrophobic cavity for pi-pi stacking contacts with the aromatic amino acids (Phe528, Phe329 and Phe659 for alpha-mannosidase I and Trp95, Tyr269, Phe312, Tyr102 for alpha-mannosidase II). The pharmacophore analysis also supports the results derived from the docking and QSAR studies. Our results suggest that the best compound to inhibit both classes of alpha-mannosidase is the compound 30, which may be used to design similar and better inhibitors to next generation drugs.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 15