Substrate Recognition in HIV-1 Protease: A Computational Study

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) protease processes and cleaves the Gag and Gag-Pol polyproteins, allowing viral maturation, and therefore is an important target for antiviral therapy. Ligand binding occurs when the flaps open, allowing access to the active site. This flexibility in flap geometry makes trapping and crystallizing structural intermediates in substrate binding challenging. In this study, we report two crystal structures of two HIV-1 protease variants bound with their corresponding nucleocapsid-p1 variant. One of the flaps in each of these structures exhibits an unusual “intermediate” conformation. Analysis of the flap-intermediate and flap-closed crystal structures reveals that the intermonomer flap movements may be asynchronous and that the flap which wraps over the P3 to P1 (P3-P1) residues of the substrate might close first. This is consistent with our hypothesis that the P3-P1 region is crucial for substrate recognition. The intermediate conformation is conserved in both the wild-type and drug-resistant variants. The structural differences between the variants are evident only when the flaps are closed. Thus, a plausible structural model for the adaptability of HIV-1 protease to recognize substrates in the presence of drug-resistant mutations has been proposed.

Download Full-text

Combatting Drug Resistance: Lessons from the viral proteases of HIV and HCV

Acta Crystallographica Section A Foundations and Advances ◽

10.1107/s2053273314098830 ◽

2014 ◽

Vol 70 (a1) ◽

pp. C116-C116

Author(s):

Celia Schiffer

Keyword(s):

Drug Resistance ◽

Hepatitis C ◽

Biological Function ◽

Substrate Recognition ◽

Atomic Resolution ◽

Inhibitor Binding ◽

Detailed Understanding ◽

Viral Proteases ◽

Hiv 1 ◽

Substrate Envelope

Drug resistance negatively impacts the lives of millions of patients and costs our society billions of dollars by limiting the longevity of many of our most potent drugs. Drug resistance can be caused by a change in the balance of molecular recognition events that selectively weakens inhibitor binding but maintains the biological function of the target. To reduce the likelihood of drug resistance, a detailed understanding of the target's function is necessary. Both structure at atomic resolution and evolutionarily constraints on its variation is required. "Resilient" targets are less susceptible to drug resistance due to their key location in a particular pathway. This rationale was derived through crystallographic studies elucidating substrate recognition and drug resistance in HIV-1 protease and Hepatitis C (HCV) NS3/4A protease. Both are key therapeutic targets and are potentially "resilient" targets where resistant mutations occur outside of the substrate binding site. To reduce the probability of drug resistance inhibitors should be designed to fit within what we define as the "substrate envelope". These principals are likely more generally applicable to other quickly evolving diseases where drug resistance is quickly evolving. http://www.umassmed.edu/schifferlab/index.aspx

Download Full-text

Using Molecular Dynamics to Investigate Substrate Recognition and Co-evolution in HIV-1 Protease

Biophysical Journal ◽

10.1016/j.bpj.2008.12.3129 ◽

2009 ◽

Vol 96 (3) ◽

pp. 598a

Author(s):

Aysegul Ozen ◽

Turkan Haliloglu ◽

Celia A. Schiffer

Keyword(s):

Molecular Dynamics ◽

Substrate Recognition ◽

Hiv 1

Download Full-text

Discovery of novel anti-HIV-1 agents based on a broadly neutralizing antibody against the envelope gp120 V3 loop: a computational study

Journal of Biomolecular Structure and Dynamics ◽

10.1080/07391102.2013.848825 ◽

2013 ◽

Vol 32 (12) ◽

pp. 1993-2004 ◽

Cited By ~ 6

Author(s):

Alexander M. Andrianov ◽

Ivan A. Kashyn ◽

Alexander V. Tuzikov

Keyword(s):

Computational Study ◽

Neutralizing Antibody ◽

V3 Loop ◽

Broadly Neutralizing Antibody ◽

Anti Hiv ◽

Hiv 1 ◽

Envelope Gp120

Download Full-text

The mystery of chemistry behind the mechanism of action of anti-HIV drugs: A docking approach at an atomic level

European Journal of Chemistry ◽

10.5155/eurjchem.12.4.432-438.2149 ◽

2021 ◽

Vol 12 (4) ◽

pp. 432-438

Author(s):

Mohammad Suhail

Keyword(s):

Immune System ◽

Mechanism Of Action ◽

Computational Study ◽

Docking Study ◽

Computational Studies ◽

Entry Inhibitors ◽

Docking Approach ◽

Hiv Drugs ◽

Anti Hiv ◽

Hiv 1

The effect of HIV-1 on a human’s immune system cannot be ignored. This is the virus that reduces the power of the immune system to fight against any disease. Of course, many anti-HIV drugs are available, and many computational studies have been done to find out their mechanism of action, but the computational study regarding the chemistry behind the mechanism of action was not done yet. Therefore, the main objective of the study was to clarify the chemistry behind the mechanism of action of commercially available anti-HIV drugs. The drugs taken in the presented study were Entry Inhibitors (EIs) and Non-nucleoside reverse transcriptase inhibitors. First, literature data was evaluated computationally to ensure the reliability of the software used for the presented study. It was found that interaction-based experimental results and computationally evaluated results of the literature data were the same. After that, by following the same procedure, a docking study was done on the drugs taken in the current study. In addition, the residues involved in the interactions of EIs and NNRTIs with their receptors were studied to determine the chemistry that acts behind the action of both. It was found that EIs and NNRTIs work differently. It was also predicted that the derivatization of both drugs could make them more effective and active. Therefore, the presented study will be very helpful in the field of medicinal science.

Download Full-text