In silico and in vitro screening to identify structurally diverse non-azole CYP51 inhibitors as potent antifungal agent |
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| Affiliation: | 1. Department of Chemistry, Annamalai University, Annamalai Nagar, Chidambaram 608002, Tamil Nadu, India;2. Department of Chemistry, College of Natural and Computational Sciences, Haramaya University, Dire Dawa, Ethiopia;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, Eskişehir 26470, Turkey;2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Doping and Narcotic Compounds Analysis Laboratory, Anadolu University, Eskişehir 26470, Turkey;3. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Erciyes University, Kayseri 38039, Turkey;4. Department of Biochemistry, Faculty of Science, Selçuk University, Konya, Turkey;5. Department of Physics, University College, Thiruvananthapuram, Kerala, India;6. Department of Biology, Faculty of Mathematics and Natural Sciences, Sam Ratulangi University, Manado 95115, North Sulawesi, Indonesia;7. The University Centre of Excellence for Biotechnology and Conservation of Wallacea, Institute for Research and Community Services, Sam Ratulangi University, Manado 95115, North Sulawesi, Indonesia;8. Department of Pharmacology, All India Institute of Medical Sciences, Rishikesh 249203, India |
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| Abstract: | The problem of resistance to azole class of antifungals is a serious cause of concern to the medical fraternity and thus there is an urgent need to identify non-azole scaffolds with high affinity for lanosterol 14α-demethylase (CYP51). In view of this we have attempted to identify novel non-azole CYP51 inhibitors through the application of pharmacophore based virtual screening and in vitro evaluation. A rigorously validated pharmacophore model comprising of 2 hydrogen bond acceptor and 2 hydrophobic features has been developed and used to mine NCI database. Out of 265 retrieved hits, NSC 1215 and 1520 have been chosen on the basis of Lipinski’s rule of five, fit and estimated values. Both the hits were docked into the active site of CYP51. In view of high fit value and CDocker score, NSC 1215 and 1520 have been subjected to in vitro microbiological assay. The result reveals that NSC 1215 and 1520 are active against Candida albicans, Candida parapsilosis, Candida tropicalis, and Aspergillus niger. In addition to this the absorption characteristics of both the hits have also been determined using the rat sac technique and permeation in order of NSC 1520 > NSC 1215 has been observed. |
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| Keywords: | Non-azoles Ligand based pharmacophore modeling Virtual screening Molecular docking |
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