Abstract
In view of the role of DHFR in design and development of antimicrobials, we have attempted to develop a rigorously validated structure-based pharmacophore model comprising of two hydrogen bond donors, one hydrogen bond acceptor and two hydrophobic features. The model was used as a query to screen the National Cancer Institute and Maybridge database leading to retrieval of many hits which were screened on the basis of estimated activity, fit value and Lipinski’s violation. Three most potent hits with zero lipinski’s violation were subjected to docking studies which resulted into visualization of potential interaction capabilities of compounds in line to pharmacophoric features. All the three hits were subjected to in vitro antimicrobial evaluation, and the order of activity against various microbial strains was found to be HTS00987 > NSC47793 > NSC5475. Since HTS00987 appeared to be most active, it was subjected to permeability studies using in vitro everted intestinal sac permeation method. The results revealed that HTS00987 has good permeability proving its potential as druggable antimicrobial agent.
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We gratefully acknowledge support for this research from Indian Council of Medical Research Centre (ICMR), New Delhi, and the authors also thank Vice Chancellor, Banasthali University for extending all the necessary facilities.
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Mishra, R., Paliwal, S., Agarwal, A. et al. Discovery of a potent broad spectrum antimicrobial agent through pharmacophore modeling, virtual screening, in vitro antimicrobial evaluation and gastrointestinal permeation studies. Med Chem Res 24, 4050–4057 (2015). https://doi.org/10.1007/s00044-015-1445-2
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DOI: https://doi.org/10.1007/s00044-015-1445-2