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Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) of thiazolone derivatives as hepatitis C virus NS5B polymerase allosteric inhibitors.
J Comput Aided Mol Des. 2008 Oct; 22(10):711-25.JC

Abstract

Three-dimensional quantitative structure-activity relationship (3D-QSAR) models for a series of thiazolone derivatives as novel inhibitors bound to the allosteric site of hepatitis C virus (HCV) NS5B polymerase were developed based on CoMFA and CoMSIA analyses. Two different conformations of the template molecule and the combinations of different CoMSIA field/fields were considered to build predictive CoMFA and CoMSIA models. The CoMFA and CoMSIA models with best predictive ability were obtained by the use of the template conformation from X-ray crystal structures. The best CoMFA and CoMSIA models gave q (2) values of 0.621 and 0.685, and r (2) values of 0.950 and 0.940, respectively for the 51 compounds in the training set. The predictive ability of the two models was also validated by using a test set of 16 compounds which gave r (pred) (2) values of 0.685 and 0.822, respectively. The information obtained from the CoMFA and CoMSIA 3D contour maps enables the interpretation of their structure-activity relationship and was also used to the design of several new inhibitors with improved activity.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Lei B
Department of Chemistry, Lanzhou University, Lanzhou 730000, China.
Du J
No affiliation info available
Li S
No affiliation info available
Liu H
No affiliation info available
Ren Y
No affiliation info available
Yao X
No affiliation info available

MeSH

Allosteric SiteCrystallography, X-RayDrug DesignEnzyme InhibitorsHydrogen BondingHydrophobic and Hydrophilic InteractionsLeast-Squares AnalysisModels, MolecularMolecular ConformationMolecular StructureQuantitative Structure-Activity RelationshipStatic ElectricityThiazolesViral Nonstructural Proteins

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18716715

Citation

Lei, Beilei, et al. "Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) of Thiazolone Derivatives as Hepatitis C Virus NS5B Polymerase Allosteric Inhibitors." Journal of Computer-aided Molecular Design, vol. 22, no. 10, 2008, pp. 711-25.
Lei B, Du J, Li S, et al. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) of thiazolone derivatives as hepatitis C virus NS5B polymerase allosteric inhibitors. J Comput Aided Mol Des. 2008;22(10):711-25.
Lei, B., Du, J., Li, S., Liu, H., Ren, Y., & Yao, X. (2008). Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) of thiazolone derivatives as hepatitis C virus NS5B polymerase allosteric inhibitors. Journal of Computer-aided Molecular Design, 22(10), 711-25. https://doi.org/10.1007/s10822-008-9230-7
Lei B, et al. Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) of Thiazolone Derivatives as Hepatitis C Virus NS5B Polymerase Allosteric Inhibitors. J Comput Aided Mol Des. 2008;22(10):711-25. PubMed PMID: 18716715.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) of thiazolone derivatives as hepatitis C virus NS5B polymerase allosteric inhibitors. AU - Lei,Beilei, AU - Du,Juan, AU - Li,Shuyan, AU - Liu,Huanxiang, AU - Ren,Yueying, AU - Yao,Xiaojun, Y1 - 2008/08/21/ PY - 2008/01/15/received PY - 2008/07/13/accepted PY - 2008/8/22/pubmed PY - 2008/12/23/medline PY - 2008/8/22/entrez SP - 711 EP - 25 JF - Journal of computer-aided molecular design JO - J Comput Aided Mol Des VL - 22 IS - 10 N2 - Three-dimensional quantitative structure-activity relationship (3D-QSAR) models for a series of thiazolone derivatives as novel inhibitors bound to the allosteric site of hepatitis C virus (HCV) NS5B polymerase were developed based on CoMFA and CoMSIA analyses. Two different conformations of the template molecule and the combinations of different CoMSIA field/fields were considered to build predictive CoMFA and CoMSIA models. The CoMFA and CoMSIA models with best predictive ability were obtained by the use of the template conformation from X-ray crystal structures. The best CoMFA and CoMSIA models gave q (2) values of 0.621 and 0.685, and r (2) values of 0.950 and 0.940, respectively for the 51 compounds in the training set. The predictive ability of the two models was also validated by using a test set of 16 compounds which gave r (pred) (2) values of 0.685 and 0.822, respectively. The information obtained from the CoMFA and CoMSIA 3D contour maps enables the interpretation of their structure-activity relationship and was also used to the design of several new inhibitors with improved activity. SN - 0920-654X UR - https://www.unboundmedicine.com/medline/citation/18716715/Comparative_molecular_field_analysis__CoMFA__and_comparative_molecular_similarity_indices_analysis__CoMSIA__of_thiazolone_derivatives_as_hepatitis_C_virus_NS5B_polymerase_allosteric_inhibitors_ L2 - https://doi.org/10.1007/s10822-008-9230-7 DB - PRIME DP - Unbound Medicine ER -