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Homology modeling, molecular dynamics, e-pharmacophore mapping and docking study of Chikungunya virus nsP2 protease

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Abstract

To date, no suitable vaccine or specific antiviral drug is available to treat Chikungunya viral (CHIKV) fever. Hence, it is essential to identify drug candidates that could potentially impede CHIKV infection. Here, we present the development of a homology model of nsP2 protein based on the crystal structure of the nsP2 protein of Venezuelan equine encephalitis virus (VEEV). The protein modeled was optimized using molecular dynamics simulation; the junction peptides of a nonstructural protein complex were then docked in order to investigate the possible protein–protein interactions between nsP2 and the proteins cleaved by nsP2. The modeling studies conducted shed light on the binding modes, and the critical interactions with the peptides provide insight into the chemical features needed to inhibit the CHIK virus infection. Energy-optimized pharmacophore mapping was performed using the junction peptides. Based on the results, we propose the pharmacophore features that must be present in an inhibitor of nsP2 protease. The resulting pharmacophore model contained an aromatic ring, a hydrophobic and three hydrogen-bond donor sites. Using these pharmacophore features, we screened a large public library of compounds (Asinex, Maybridge, TOSLab, Binding Database) to find a potential ligand that could inhibit the nsP2 protein. The compounds that yielded a fitness score of more than 1.0 were further subjected to Glide HTVS and Glide XP. Here, we report the best four compounds based on their docking scores; these compounds have IDs of 27943, 21362, ASN 01107557 and ASN 01541696. We propose that these compounds could bind to the active site of nsP2 protease and inhibit this enzyme. Furthermore, the backbone structural scaffolds of these four lead compounds could serve as building blocks when designing drug-like molecules for the treatment of Chikungunya viral fever.

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Acknowledgments

The authors like to thank the Department of Bioinformatics, Alagappa University, Karaikudi, India for its support and providing the facilities for this work.

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Authors and Affiliations

  1. Department of Bioinformatics , Alagappa University, Karaikudi, 63003, India

    Kh. Dhanachandra Singh, Palani Kirubakaran, Karthikeyan Muthusamy & Jeyaraman Jeyakanthan

  2. Bioinformatics Centre, Pondicherry University, Pondicherry, 605 014, India

    Shanthi Nagarajan

  3. Bioinformatics Centre and Computational Biology Laboratory, Department of Bioinformatics, Bharathiar University, Coimbatore, 641 046, India

    Sugunadevi Sakkiah

  4. CAS, Biophysics and Crystallography, University of Madras, Chennai, 600025, India

    Devadasan Velmurgan

Authors
  1. Kh. Dhanachandra Singh
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  2. Palani Kirubakaran
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  4. Sugunadevi Sakkiah
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Correspondence to Jeyaraman Jeyakanthan.

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Kh. Dhanachandra Singh, Palani Kirubakaran, and Shanthi Nagarajan contributed equally to this work.

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Singh, K.D., Kirubakaran, P., Nagarajan, S. et al. Homology modeling, molecular dynamics, e-pharmacophore mapping and docking study of Chikungunya virus nsP2 protease. J Mol Model 18, 39–51 (2012). https://doi.org/10.1007/s00894-011-1018-3

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  • DOI: https://doi.org/10.1007/s00894-011-1018-3

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