Study Sheds Light on the Biophysics of HIV Treatment Drug, lamivudine

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The rapid emergence of different drug resistant strains of HIV-1 reverse transcriptase in relation to viral pathogenesis as well as drug development remains of primary interest for young health scientist, Mr Soumendranath Bhakat.

Born in India, Bhakat is a PhD candidate in the Molecular Modelling and Drug Design Research Laboratory headed by Professor Mahmoud Soliman, the new Dean and Head of the School of Health Sciences.

Bhakat presented his compelling Masters research at the 2014 College of Health Sciences Research Symposium.  It was titled: “An integrated molecular dynamics, principal component analysis and residue interaction network approach reveals the impact of M184V mutation on HIV reverse transcriptase resistance to lamivudine”.

The study reported the first account of the molecular impact of M184V mutation on HIV reverse transcriptase resistance to lamivudine – the drug prescribed for the treatment of HIV infection and hepatitis B infection – using a combination of molecular dynamics simulation, binding free energy analysis, principle component analysis and residue interaction networks.

Results from the study confirmed that M184V mutation leads to steric conflict between lamivudine and the beta-branched side chain of valine (amino acid), decreases the ligand lamivudine binding affinity when compared to the wild type, changes the overall conformational landscape of the protein and distorts the native enzyme residue-residue interaction network.

Bhakat said: ‘The comprehensive molecular insight gained from this study should be of great importance in understanding drug resistance against HIV reverse transcriptase as well as assisting in the design of novel reverse transcriptase inhibitors with high ligand efficacy on resistant strains.’

‘The study sheds light on the molecular mechanism of M184V resistance on lamivudine and related changes in conformational landscape of drug binding as well as overall protein conformation. This insight will act as a cornerstone to design novel nucleoside analog reverse transcriptase inhibitors against drug-resistant strains,’ he added.

The study was published last year in one of the top journals of the Royal Society of Chemistry, Molecular Biosystems.

Bhakat, who also has a Bachelor of Pharmacy degree from Birla Institute of Technology in Mesra, India, said the fact that research led to new discoveries which affect a large portion of humanity in a positive way made him passionate about his work.

‘The open academic atmosphere of UKZN nurtures critical thinking which is complemented well by its infrastructure, faculty and scholarship and thus provides an ideal atmosphere for research excellence.’

Determined to produce further research that will be published widely in leading international journals, Bhakat said he would continue his work on biophysics, computational biology and drug discovery in order to develop novel drug candidates as well as understanding molecular basis of protein folding and dynamics.

Lunga Memela