Comparative QSAR studies on peptide deformylase inhibitors |
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Authors: | Ji Young Lee Munikumar Reddy Doddareddy Yong Seo Cho Hyunah Choo Hun Yeong Koh Jae-Hoon Kang Kyoung Tai No Ae Nim Pae |
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Institution: | (1) Biochemicals Research Center, Korea Institute of Science and Technology, P.O. Box 131, Cheongryang, Seoul, 130-650, South Korea;(2) Department of Chemistry, Inha University, 253 Yonghyungdong Namgu, Inchon, 402-751, South Korea;(3) Research Laboratories, ILDONG Pharmaceutical Co., 260-5, Eonnam-Dong, Giheung-Gu, Yongin, Gyeonggi-Do, 449-915, South Korea;(4) Department of Biotechnology, Yonsei University, 220, Sinchon-dong, Seodaemun-gu, Seoul, 120-749, South Korea |
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Abstract: | Comparative quantitative structure–activity relationship (QSAR) analyses of peptide deformylase (PDF) inhibitors were performed
with a series of previously published (British Biotech Pharmaceuticals, Oxford, UK) reverse hydroxamate derivatives having
antibacterial activity against Escherichia coli PDF, using 2D and 3D QSAR methods, comparative molecular field analysis (CoMFA), comparative molecular similarity indices
analysis (CoMSIA), and hologram QSAR (HQSAR). Statistically reliable models with good predictive power were generated from
all three methods (CoMFA r
2 = 0.957, q
2 = 0.569; CoMSIA r
2 = 0.924, q
2 = 0.520; HQSAR r
2 = 0.860, q
2 = 0.578). The predictive capability of these models was validated by a set of compounds that were not included in the training
set. The models based on CoMFA and CoMSIA gave satisfactory predictive r
2 values of 0.687 and 0.505, respectively. The model derived from the HQSAR method showed a low predictability of 0.178 for
the test set. In this study, 3D prediction models showed better predictive power than 2D models for the test set. This might
be because 3D information is more important in the case of datasets containing compounds with similar skeletons. Superimposition
of CoMFA contour maps in the active site of the PDF crystal structure showed a meaningful correlation between receptor–ligand
binding and biological activity. The final QSAR models, along with information gathered from 3D contour and 2D contribution
maps, could be useful for the design of novel active inhibitors of PDF.
Figure Superimposition of comparative molecular field analysis (CoMFA) contour plot in the active site of peptide deformylase (PDF) |
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Keywords: | PDF QSAR CoMFA CoMSIA HQSAR |
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