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

• Tipo: Artigo em Revista Científica Internacional
• Data: 2012

Autores

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

Revista

Título: Bioorganic and Medicinal Chemistry

Vol. 20

Páginas: 6945-6959

ISSN: 0968-0896

Editora: Elsevier

Indexação

ISI Web of Knowledge - 7 Citações

Scopus - 8 Citações

Classificação Científica

FOS: Ciências exactas e naturais > Química

Outras Informações

ID Authenticus: 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.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 15