Rational design of new antituberculosis agents: receptor-independent four-dimensional quantitative structure-activity relationship analysis of a set of isoniazid derivatives.
A 4D-QSAR analysis was carried out for a set of 37 hydrazides whose minimum inhibitory concentrations against M. tuberculosis var. bovis were evaluated. These ligands are thought to act like isoniazid in mycolic acid biosynthesis. Results indicate that nonpolar groups in the acyl moiety of ligands markedly decrease biological activity. Molecular modifications of the ligand NAD moiety, including nonpolar groups and hydrogen bond donor and acceptor groups, seemingly improve ligand interactions with amino acid residues of the InhA active site.
Pasqualoto
Kerly F M
KF
LAPEN, Departamento de Farmácia, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, Av. Prof. Lineu Prestes 580, Bloco 13 sup., São Paulo, SP 05508-900, Brazil. kerly@netpoint.com.br
Ferreira
Elizabeth I
EI
Santos-Filho
Osvaldo A
OA
Hopfinger
Anton J
AJ
D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D007538:Isoniazid / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D021281:Quantitative Structure-Activity Relationship
D000995:Antitubercular Agents; D007538:Isoniazid