Insights into the structural determinants for selective inhibition of nitric oxide synthase isoforms

• Type: Article in International Scientific Journal
• Date: 2013

Authors

Bruno L Oliveira (Author) Other; Irina S Moreira (Author) Other; Pedro A Fernandes (Author) FCUP; Maria J Ramos (Author) FCUP; Isabel Santos (Author) Other; Joao D G Correia (Author) Other

Journal

Title: Journal Of Molecular Modeling

Vol. 19

Pages: 1537-1551

ISSN: 1610-2940

Publisher: Springer Nature

Indexing

ISI Web of Knowledge - 13 Citations

Scopus - 13 Citations

Scientific classification

FOS: Natural sciences > Chemical sciences

Other information

Authenticus ID: P-005-29A

DOI: 10.1007/s00894-012-1677-8

Abstract (EN): Selective inhibition of the nitric oxide synthase isoforms (NOS) is a promising approach for the treatment of various disorders. However, given the high active site conservation among all NOS isoforms, the design of selective inhibitors is a challenging task. Analysis of the X-ray crystal structures of the NOS isoforms complexed with known inhibitors most often gives no clues about the structural determinants behind the selective inhibition since the inhibitors share the same binding conformation. Aimed at a better understanding of the structural factors responsible for selective inhibition of NOS isoforms we have performed MD simulations for iNOS, nNOS and eNOS complexed with N-omega-NO2-L-Arg (1), and with the aminopyridine derivatives 2 and 3. The slightly better selectivity of 1 for nNOS may be assigned to the presence of extra charge-charge interactions due to its "extended" conformation. While the high affinity of 2 for iNOS can be explained by the formation of an iNOS-specific subpocket upon binding, the lack of affinity for eNOS is associated to a conformational change in Glu363. The strong van der Waals and electrostatic interactions between 3 and the active site of nNOS are most likely responsible for its higher affinity for this isoform. Owing to the elongated and narrow binding pocket of iNOS, the correct positioning of 3 over the heme group is difficult, which may account for its lower affinity toward this isoform. Brought together, our results might help to rationalize the design of selective NOS inhibitors.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 15