期刊
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
卷 -, 期 -, 页码 -出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/07391102.2023.2220808
关键词
Fluconazole; analogue based drug designing; molecular docking; simulations; combination studies
Extensive research is necessary to develop new therapeutic strategies for fighting against aggressive fungal infections. This study generated and evaluated analogues of Fluconazole (FLZ) to identify compounds with better potency against fungal-borne infections. Two analogues, 6f and 8f, showed potential for further evaluation based on their molecular docking scores and exhibited low antifungal activities compared to FLZ.
The drugs fighting against aggressive fungal infections are in limited number, therefore, extensive research is obligatory to develop new therapeutic strategies. Fluconazole (FLZ) is a clinically approved drug, but resistant drug against most fungal pathogens, thus it is vital to identify more compounds that can better check the fungal growth. Analogue-based drug designing is a quick and economical way since it has inherent drug-like properties of marketed drugs. This study aims to generate and evaluate analogues of FLZ with better potency against fungal-borne infections. A total of 3307 analogues of FLZ were developed from six scaffold structures. Only 390 compounds passed Lipinski's rule, of which 247 analogues exhibited lower docking scores than FLZ with 5FSA. These inhibitors were further subjected to pharmacokinetics property evaluation and cytotoxicity test and it was found that only 46 analogues were suitable for further evaluation. Based on the molecular docking score of the best two analogues, 6f (-12.7 kcal/mol) and 8f (-12.8 kcal/mol) were selected for molecular dynamics and in-vitro studies. Antifungal activities of both compounds against 4 strains of Candida albicans were evaluated by disc diffusion assay and micro broth dilution assay and Minimum inhibitory concentrations (MICs) for 6f and 8f were observed as 256 mu g/ml against 4719, 4918 and 5480 strains but the MIC was extended to 512 mu g/ml for strain 3719. Both analogues exhibited low antifungal activities as compared to FLZ (8-16 mu g/ml). The interaction of 6f with Mycostatin was also performed using a chequerboard assay that was found additive.Communicated by Ramaswamy H. Sarma
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