ABSTRACT
To clarify the important functional residues in the active site of N-myristoyltransferase (NMT), a novel antifungal drug target, and to guide the design of specific inhibitors, multiple sequence alignments were performed on the NMT family and thus evolutionary trace was constructed. The important functional residues in myristoyl CoA binding site, catalytic center and inhibitor binding site of NMT family were identified by ET analysis. The trace residues were mapped onto the active site of CaNMT. Trpl26, Asn175 and Thr211 are highly conserved trace residues and do not interact with current NMT inhibitors, which are potential novel drug binding sites for the novel inhibitor design. Pro338, Leu350, Ile352 and Ala353 are class-specific trace residues, which are important for the optimization of current NMT inhibitors. The trace residues identified by ET analysis are of great importance to study the structure-function relationship and also to guide the design of specific inhibitors.
Subject(s)
Animals , Humans , Acyl Coenzyme A , Metabolism , Acyltransferases , Chemistry , Genetics , Metabolism , Amino Acid Sequence , Binding Sites , Conserved Sequence , Enzyme Inhibitors , Chemistry , Pharmacology , Evolution, Molecular , Imidazoles , Chemistry , Pharmacology , Models, Molecular , Molecular Sequence Data , Oligopeptides , Chemistry , Pharmacology , Phylogeny , Protein Structure, Tertiary , Sequence Homology, Amino AcidABSTRACT
<p><b>AIM</b>A series of triazole antifungal agents were synthesized to search for novel triazole antifungal agents with more potent activity, less toxicity and broader spectrum.</p><p><b>METHODS</b>Twenty-one 1-(1H-1, 2, 4-triazolyl)-2-(2, 4-diflurophenyl)-3-(4-substituted-1-piperazinyl)-2-propanols were synthesized, on the basis of the three dimensional structure of P450 cytochrome 14alpha-sterol demethylase (CYP51) and their antifungal activities were also evaluated.</p><p><b>RESULTS</b>Results of preliminary biological tests showed that most of title compounds exhibited activity against the eight common pathogenic fungi to some extent and the activities against deep fungi were higher than that against shallow fungi. In general, phenyl and pyridinyl analogues showed higher antifungal activity than that of the phenylacyl analogues.</p><p><b>CONCLUSION</b>Several title compounds showed higher antifungal activities than fluconazole and terbinafine. Compound VIII-1, 4, 5 and IX-3 showed the best antifungal activity with broad antifungal spectrum and were chosen for further study.</p>