Structural Chemistry

, Volume 30, Issue 5, pp 1715–1727 | Cite as

Molecular alteration in drug susceptibility against subtype B and C-SA HIV-1 proteases: MD study

  • Amit Kumar Halder
  • Bahareh HonarparvarEmail author
Original Research


HIV-1 protease (HIV PR) is one of the most promising targets for anti-HIV drug discovery. Extensive anti-HIV drug discovery research was focused on HIV-1 subtype B protease though FDA-approved protease inhibitors (PIs) generally exhibit altered biological activities against other protease subtypes such as South African subtype C (C-SA) protease that is prevalent in sub-Saharan Africa. Recent experimental reports highlight the differences in dynamic behaviors between these two protease subtypes. Herein, the dynamics of three FDA approved PIs, namely atazanavir (ATV), darunavir (DRV), and ritonavir (RTV), were thoroughly analyzed for both subtypes B and C protease complexes using molecular dynamic (MD) simulation in explicit solvent. The comparative MD post-analyses through flap dynamics, cross-correlation analyses, principal component analyses (PCA), per residue decomposition analyses, and MM-GBSA binding free energy analyses, revealed the altered responses observed in the complexes of these PIs in these two protease subtypes. The calculated theoretical binding energy analyses are consistent with the experiment to a considerable extent. Theoretical binding energies combined with flap dynamics appear to correspond to altered drug susceptibility against subtype B and C-SA HIV-1 proteases. The current analyses provide useful insight on the mechanism of action of PIs against these two different HIV-1 protease subtypes which will be helpful in developing new anti-protease compounds.


HIV-1 protease (HIV PR) Protease inhibitors (PIs) Molecular dynamic (MD) simulation Flap dynamics Binding free energy 



We thank the CHPC ( for providing computational resources.

Funding information

This work was financially supported by the NRF, College of Health Sciences, at University of KwaZulu Natal (UKZN), and Aspen-Pharmacare.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

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ESM 1 (RAR 576 kb)
11224_2019_1305_MOESM2_ESM.docx (232 kb)
ESM 2 (DOCX 231 kb)


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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.School of Health SciencesUniversity of KwaZulu-NatalDurbanSouth Africa

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