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Title |
Optimization of Benzoisothiazole dioxide inhibitory activity of the NS5B polymerase of HCV genotype 4 using ligand-steered homological modeling, reaction-driven scaffold-hopping and E-novo workflow |
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Authors |
Amr Hamed Mahmoud*, Khaled Abouzid Mohamed Abouzid, Dalal Abd El Rahman Abou El Ella, Mohamed Abdel Hamid Ismail |
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Affiliation |
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt
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amr.hamed@pharm.asu.edu; *Corresponding authors
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Article Type |
Hypothesis
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Date |
Received November 18, 2011; Accepted November 18, 2011; Published December 10, 2011
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Abstract |
Infection caused by hepatitis C virus (HCV) is a significant world health problem for which novel therapies are in urgent demand. The virus is highly prevalent in the Middle East and Africa particularly Egypt with more than 90% of infections due to genotype 4. Nonstructural (NS5B) viral proteins have emerged as an attractive target for HCV antivirals discovery. A potent class of inhibitors having benzisothiazole dioxide scaffold has been identified on this target, however they were mainly active on genotype 1 while exhibiting much lowered activity on other genotypes due to the high degree of mutation of its binding site. Based on this fact, we employed a novel strategy to optimize this class on genotype 4. This strategy depends on using a refined ligand-steered homological model of this genotype to study the mutation binding energies of the binding site amino acid residues, the essential features for interaction and provide a structure-based pharmacophore model that can aid optimization. This model was applied on a focused library which was generated using a reaction-driven scaffold-hopping strategy. The hits retrieved were subjected to E-novo pipeline pilot optimization workflow that employs R-group enumeration, core-constrained protein docking using modified CDOCKER and finally ranking of poses using an accurate molecular mechanics generalized Born with surface area method.
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Citation |
Mahmoud et al.
Bioinformation 7(7): 328-333 (2011) |
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Edited by |
P Kangueane
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ISSN |
0973-2063
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Publisher |
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Copyright |
Publisher
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Copyright Transfer Agreement |
The authors of published articles in Bioinformation automatically transfer the copyright to the publisher upon formal acceptance. However, the authors reserve right to use the information contained in the article for non commercial purposes.
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License |
This is an open-access article, which permits unrestricted use, distribution, and reproduction in any medium, for non-commercial purposes, provided the original author and source are credited.
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