Free Energy Component Analysis for Drug Design:  A Case Study of HIV-1 Protease−Inhibitor Binding

2001 ◽  
Vol 44 (25) ◽  
pp. 4325-4338 ◽  
Author(s):  
Parul Kalra ◽  
T. Vasisht Reddy ◽  
B. Jayaram
Keyword(s):  
Free Energy ◽  
Drug Design ◽  
Protease Inhibitor ◽  
Component Analysis ◽  
Inhibitor Binding ◽  
Energy Component ◽  
Hiv 1

Binding Free Energy Contributions of Interfacial Waters in HIV-1 Protease/Inhibitor Complexes

2006 ◽  
Vol 128 (36) ◽  
pp. 11830-11839 ◽  
Author(s):  
Yipin Lu ◽  
Chao-Yie Yang ◽  
Shaomeng Wang
Keyword(s):  
Free Energy ◽  
Protease Inhibitor ◽  
Binding Free Energy ◽  
Hiv 1

In Silico Investigation of a HIV-1 Vpr Inhibitor Binding Site: Potential for Virtual Screening and anti-HIV Drug Design

2014 ◽  
pp. n/a-n/a ◽  
Author(s):  
Sy Bing Choi ◽  
Yee Siew Choong ◽  
Akiko Saito ◽  
Habibah A. Wahab ◽  
Nazalan Najimudin ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Drug Design ◽  
Binding Site ◽  
In Silico ◽  
Inhibitor Binding ◽  
Anti Hiv ◽  
Hiv 1

scholarly journals Non-Active Site Mutants of HIV-1 Protease Influence Resistance and Sensitisation Towards Protease Inhibitors

2020 ◽  
Author(s):  
Tomas Bastys ◽  
Vytautas Gapsys ◽  
Hauke Walter ◽  
Eva Heger ◽  
Nadezhda T Doncheva ◽  
...  
Keyword(s):  
Hydrogen Bond ◽  
Protease Inhibitor ◽  
Protease Inhibitors ◽  
Active Site ◽  
Binding Pocket ◽  
Antiretroviral Drugs ◽  
Response To Therapy ◽  
Inhibitor Binding ◽  
Ic50 Values ◽  
Hiv 1

Abstract Background HIV-1 can develop resistance to antiretroviral drugs, mainly through mutations within the target regions of the drugs. In HIV-1 protease, a majority of resistance-associated mutations that develop in response to therapy with protease inhibitors are found in the protease’s active site that serves also as a binding pocket for the protease inhibitors, thus directly impacting the protease-inhibitor interactions. Some resistance-associated mutations, however, are found in more distant regions, and the exact mechanisms how these mutations affect protease-inhibitor interactions are unclear. Furthermore, some of these mutations, e.g. N88S and L76V, do not only induce resistance to the currently administered drugs, but contrarily induce sensitivity towards other drugs. In this study, mutations N88S and L76V, along with three other resistance-associated mutations, M46I, I50L, and I84V, are analysed by means of molecular dynamics simulations to investigate their role in complexes of the protease with different inhibitors and in different background sequence contexts. Results Using these simulations for alchemical calculations to estimate the effects of mutations M46I, I50L, I84V, N88S, and L76V on binding free energies shows they are in general in line with the mutations’ effect on IC50 values. For the primary mutation L76V, however, the presence of a background mutation M46I in our analysis influences whether the unfavourable effect of L76V on inhibitor binding is sufficient to outweigh the accompanying reduction in catalytic activity of the protease. Finally, we show that L76V and N88S changes the hydrogen bond stability of these residues with residues D30/K45 and D30/T31/T74, respectively. Conclusions We demonstrate that estimating the effect of both binding pocket and distant mutations on inhibitor binding free energy using alchemical calculations can reproduce their effect on the experimentally measured IC50 values. We show that distant site mutations L76V and N88S affect the hydrogen bond network in the protease’s active site, which offers an explanation for the indirect effect of these mutations on inhibitor binding. This work thus provides valuable insights on interplay between primary and background mutations and mechanisms how they affect inhibitor binding.

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