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J Biomol Struct Dyn. 2018 Feb;36(2):486-503. doi: 10.1080/07391102.2017.1281762. Epub 2017 Feb 1.

Molecular dynamics and MM/GBSA-integrated protocol probing the correlation between biological activities and binding free energies of HIV-1 TAR RNA inhibitors.

Author information

1
a Molecular Modeling and Medicinal Chemistry Group, Department of Chemistry , University College of Science, Osmania University , Hyderabad 500 007 , Telangana , India.
2
b Department of Chemistry , Nizam College, Osmania University , Hyderabad 500 001 , Telangana , India.

Abstract

The interaction of HIV-1 transactivator protein Tat with its cognate transactivation response (TAR) RNA has emerged as a promising target for developing antiviral compounds and treating HIV infection, since it is a crucial step for efficient transcription and replication. In the present study, molecular dynamics (MD) simulations and MM/GBSA calculations have been performed on a series of neamine derivatives in order to estimate appropriate MD simulation time for acceptable correlation between ΔGbind and experimental pIC50 values. Initially, all inhibitors were docked into the active site of HIV-1 TAR RNA. Later to explore various conformations and examine the docking results, MD simulations were carried out. Finally, binding free energies were calculated using MM/GBSA method and were correlated with experimental pIC50 values at different time scales (0-1 to 0-10 ns). From this study, it is clear that in case of neamine derivatives as simulation time increased the correlation between binding free energy and experimental pIC50 values increased correspondingly. Therefore, the binding energies which can be interpreted at longer simulation times can be used to predict the bioactivity of new neamine derivatives. Moreover, in this work, we have identified some plausible critical nucleotide interactions with neamine derivatives that are responsible for potent inhibitory activity. Furthermore, we also provide some insights into a new class of oxadiazole-based back bone cyclic peptides designed by incorporating the structural features of neamine derivatives. On the whole, this approach can provide a valuable guidance for designing new potent inhibitors and modify the existing compounds targeting HIV-1 TAR RNA.

KEYWORDS:

HIV-1 TAR RNA; MD simulations; MM/GBSA; binding free energies; cyclic peptides; neamine derivatives

PMID:
28081678
DOI:
10.1080/07391102.2017.1281762
[Indexed for MEDLINE]

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