Molecular modeling of azole antifungal agents active against Candida albicans. 1. A comparative molecular field analysis study

Tafi, A; Anastassopoulou, J; Theophanides, T; Botta, M; Corelli, F; Massa, S; Artico, M; Costi, R; Di Santo, R; Ragno, R

dc.contributor.author	Tafi, A	en
dc.contributor.author	Anastassopoulou, J	en
dc.contributor.author	Theophanides, T	en
dc.contributor.author	Botta, M	en
dc.contributor.author	Corelli, F	en
dc.contributor.author	Massa, S	en
dc.contributor.author	Artico, M	en
dc.contributor.author	Costi, R	en
dc.contributor.author	Di Santo, R	en
dc.contributor.author	Ragno, R	en
dc.date.accessioned	2014-03-01T11:44:25Z
dc.date.available	2014-03-01T11:44:25Z
dc.date.issued	1996	en
dc.identifier.issn	0022-2623	en
dc.identifier.uri	https://dspace.lib.ntua.gr/xmlui/handle/123456789/36941
dc.subject.classification	Chemistry, Medicinal	en
dc.subject.other	bifonazole	en
dc.subject.other	pyrrole derivative	en
dc.subject.other	analytic method	en
dc.subject.other	antifungal activity	en
dc.subject.other	candida albicans	en
dc.subject.other	fungus growth	en
dc.subject.other	growth inhibition	en
dc.subject.other	hydrophobicity	en
dc.subject.other	hydroxylation	en
dc.subject.other	molecular model	en
dc.subject.other	nonhuman	en
dc.subject.other	review	en
dc.subject.other	structure activity relation	en
dc.subject.other	structure analysis	en
dc.subject.other	X ray crystallography	en
dc.subject.other	Antifungal Agents	en
dc.subject.other	Candida albicans	en
dc.subject.other	Models, Molecular	en
dc.subject.other	Structure-Activity Relationship	en
dc.title	Molecular modeling of azole antifungal agents active against Candida albicans. 1. A comparative molecular field analysis study	en
heal.type	other	en
heal.identifier.primary	10.1021/jm950385+	en
heal.identifier.secondary	http://dx.doi.org/10.1021/jm950385+	en
heal.language	English	en
heal.publicationDate	1996	en
heal.abstract	A series of 56 azole antifungal agents belonging to chemically diverse families related to bifonazole, one of the antimycotic drugs of clinical use, were investigated using the comparative molecular field analysis (CoMFA) paradigm. The studied compounds, which have been already synthesized and reported to be active in vitro against Candida albicans, were divided into a training set and a test set. The training set consisted of 40 molecules from all the different structural classes. Due to the lack of experimental structural data on these derivatives, molecular mechanics techniques were used to obtain putative active conformations for all the compounds. The correctness of this molecular modeling work was confirmed a posteriori by comparison with structural data of the analog 2w obtained by X-ray crystallographic analysis (Massa, S.; et al. fur. J. Med. Chem. 1992, 27, 495-502). Two different alignment rules of the training set molecules were used in this study and are based on the assumption that according to published results on azole antifungal agents, all the studied compounds exert their inhibitory activity through the coordination of their azole moiety to the protoporphyrin iron atom of the fungal lanosterol 14 alpha-demethylase enzyme. The predictive ability of each resultant CoMFA model was evaluated using a test set consisting of 16 representative compounds that belong to all the different structural classes. The best 3D-quantitative structure-activity relationship model found yields significant cross-validated, conventional, and predictive r(2) values equal to 0.57, 0.95, and 0.69, respectively. The average absolute error of predictions of this model is 0.30 log units, and the structural moieties of the studied antifungal agents which are thought to contribute to the biological activity were identified. The predictive capability of this model could be exploited in further synthetic studies on antifungal azoles. Furthermore, the results obtained by using two different alignments of the inhibitors suggest that the binding mode of these molecules involves both a coordination to the iron protoporphyrin atom and an additional, likewise relevant, hydrophobic interaction with the active site.	en
heal.publisher	AMER CHEMICAL SOC	en
heal.journalName	Journal of Medicinal Chemistry	en
dc.identifier.doi	10.1021/jm950385+	en
dc.identifier.isi	ISI:A1996UA57700006	en
dc.identifier.volume	39	en
dc.identifier.issue	6	en
dc.identifier.spage	1227	en
dc.identifier.epage	1235	en