Combined structure-based pharmacophore, virtual screening, and 3D-QSAR studies of structural diverse dehydrosqualene syn
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Med Chem Res DOI 10.1007/s00044-012-0465-4
ORIGINAL RESEARCH
Combined structure-based pharmacophore, virtual screening, and 3D-QSAR studies of structural diverse dehydrosqualene synthase inhibitors Fei Peng • Aihua Peng • Youfu Luo • Wei Huang Bo Han • Xiaoyan Yang • Wei Ang • Tao Yang • Mingli Xiang • Cheng Peng • Gu He
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Received: 1 November 2012 / Accepted: 31 December 2012 Ó Springer Science+Business Media New York 2013
Abstract Dehydrosqualene synthase (CrtM) is a key enzyme in the synthesis of presqualene diphosphate in Staphylococcus aureus. In the current study, a combination of structure-based pharmacophore and 3D-QSAR methods are used to clarify the essential quantitative structure–activity relationship (QSAR) of known CrtM inhibitors; the multicomplex-based pharmacophore (MCBP) guided method has been suggested to generate a comprehensive pharmacophore of CrtM based on twenty crystal structures of CrtM inhibitor complex. Performances of the MCBP-based virtual screening approach were applied to screen specs chemical databases (202, 408 compounds). Thirty-eight compounds were selected from the final hits and should be shifted to experimental studies. The MCBP model has been successfully used to identify the bioactive conformation and align 24 structurally diverse CrtM inhibitors. The QSAR analyses have been performed on these CrtM inhibitors based on MCBP guided alignment. These results may provide important information for further design and discovery of novel CrtM inhibitors. Electronic supplementary material The online version of this article (doi:10.1007/s00044-012-0465-4) contains supplementary material, which is available to authorized users. F. Peng A. Peng Y. Luo (&) X. Yang W. Ang T. Yang M. Xiang G. He (&) State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People’s Republic of China e-mail: [email protected] G. He e-mail: [email protected] W. Huang B. Han C. Peng State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 610041, People’s Republic of China
Keywords Pharmacophore 3D-QSAR Dehydrosqualene synthase Virtual screening
Introduction Staphylococcus aureus is a group of bacteria that can cause a number of infectious diseases. Patients with infections due to S. aureus often need antibiotic treatment. Infections due to normal strains of S. aureus are often treated with flucloxacillin, but this is ineffective against MRSA, or methicillinresistant S. aureus, which is particularly dangerous because it is resistant to numerous antibiotics, including methicillin, penicillin, erythromycin, and ciprofloxacin. Infections with MRSA are most common in hospitals and other institutional health-care settings. However, its outbreaks are appearing increasingly in the community (Novick, 2008). The US Centers for Disease Control and Prevention (CDC) estimates that about 12 % of MRSA infections are now community associated. Infectio
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