Rajendram V Rajnarayanan

Publications (2)5.87 Total impact

• Article: In-silico screening using flexible ligand binding pockets: a molecular dynamics-based approach.

  Dakshanamurthy Sivanesan, Rajendram V Rajnarayanan, Jason Doherty, Nagarajan Pattabiraman
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  ABSTRACT: In-silico screening of flexible ligands against flexible ligand binding pockets (LBP) is an emerging approach in structure-based drug discovery. Here, we describe a molecular dynamics (MD) based docking approach to investigate the influence on the high-throughput in-silico screening of small molecules against flexible ligand binding pockets. In our approach, an ensemble of 51 energetically favorable structures of the LBP of human estrogen receptor alpha (hERalpha) were collected from 3 ns MD simulations. In-silico screening of 3500 endocrine disrupting compounds against these flexible ligand binding pockets resulted in thousands of ER-ligand complexes of which 582 compounds were unique. Detailed analysis of MD generated structures showed that only 17 of the LBP residues significantly contribute to the overall binding pocket flexibility. Using the flexible LBP conformations generated, we have identified 32 compounds that bind better to the flexible ligand-binding pockets compared to the crystal structure. These compounds, though chemically divergent, are structurally similar to the natural hormone. Our MD-based approach in conjunction with grid-based distributed computing could be applied routinely for in-silico screening of large databases against any given target.
  Journal of Computer-Aided Molecular Design 05/2005; 19(4):213-28. · 3.39 Impact Factor
• Article: "Teaching old drugs to kill new bugs": structure-based discovery of anti-SARS drugs.

  Rajendram V Rajnarayanan, Sivanesan Dakshanamurthy, Nagarajan Pattabiraman
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  ABSTRACT: Severe acute respiratory syndrome (SARS) main protease or 3C-like protease (3CLpro) is essential for the propagation of the coronaviral life cycle and is regarded as one of the main targets for structure-based anti-SARS drug design. It is an attractive approach to find new uses for old drugs as they have already been through extensive clinical testing and could easily be accelerated for clinical approval. Briefly, we performed virtual screening of a database of small molecules against SARS 3CLpro, analyzed inhibitor-protease complexes, and identified several covalent and non-covalent inhibitors. Several old drugs that bind to SARS 3CLpro active site were selected and in silico derivatized to generate covalent irreversible inhibitors with enhanced affinity. Furthermore, we show that pharmacophores derived from clusters of compounds resulting out of virtual screening could be useful probes for future structure-activity relationship studies (SARs) and fine-tune the lead molecules identified.
  Biochemical and Biophysical Research Communications 09/2004; 321(2):370-8. · 2.48 Impact Factor