Importance of polar solvation and configurational entropy for design of antiretroviral drugs targeting HIV-1 protease.

Kar, Parimal; Lipowsky, Reinhard; Knecht, Volker

doi:10.1021/jp3085292

Cited by 53Computational Drug Discovery MethodsHIV/AIDS drug development and treatmentProtein Structure and Dynamics

Importance of polar solvation and configurational entropy for design of antiretroviral drugs targeting HIV-1 protease.

Kar, Parimal, Lipowsky, Reinhard, Knecht, Volker·2013·The Journal of Physical Chemistry B

DOI 10.1021/jp3085292

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Abstract

Both KNI-10033 and KNI-10075 are high affinity preclinical HIV-1 protease (PR) inhibitors with affinities in the picomolar range. In this work, the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method has been used to investigate the potency of these two HIV-1 PR inhibitors against the wild-type and mutated proteases assuming that potency correlates with the affinity of the drugs for the target protein. The decomposition of the binding free energy reveals the origin of binding affinities or mutation-induced affinity changes. Our calculations indicate that the mutation I50V causes drug resistance against both inhibitors. On the other hand, we predict that the mutant I84V causes drug resistance against KNI-10075 while KNI-10033 is more potent against the I84V mutant compared to wild-type protease. Drug resistance arises mainly from unfavorable shifts in van der Waals interactions and configurational entropy. The latter indicates that neglecting changes in configurational entropy in the computation of relative binding affinities as often done is not appropriate in general. For the bound complex PR(I50V)-KNI-10075, an increased polar solvation free energy also contributes to the drug resistance. The importance of polar solvation free energies is revealed when interactions governing the binding of KNI-10033 or KNI-10075 to the wild-type protease are compared to the inhibitors darunavir or GRL-06579A. Although the contributions from intermolecular electrostatic and van der Waals interactions as well as the nonpolar component of the solvation free energy are more favorable for PR-KNI-10033 or PR-KNI-10075 compared to PR-DRV or PR-GRL-06579A, both KNI-10033 and KNI-10075 show a similar affinity as darunavir and a lower binding affinity relative to GRL-06579A. This is because of the polar solvation free energy which is less unfavorable for darunavir or GRL-06579A relative to KNI-10033 or KNI-10075. The importance of the polar solvation as revealed here highlights that structural inspection alone is not sufficient for identifying the key contributions to binding affinities and affinity changes for the design of drugs but that solvation effects must be taken into account. A detailed understanding of the molecular forces governing binding and drug resistance might assist in the design of new inhibitors against HIV-1 PR variants that are resistant against current drugs.

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The desolvation of polar or charged groups of the protein or ligand is unfavorable to binding when the formed solute-solvent interactions are not effectively satisfied upon protein-ligand binding.
“At the same time, the desolvation of polar or charged groups of the protein or ligand is unfavorable to binding when the formed solute–solvent interactions are not effectively satisfied upon the protein–ligand binding (Blaber et al., 1993; Kar et al., 2013).”
From Empirical scoring functions for structure-based virtual screening: applications, critical aspects, and challenges (2018) · cites this paper as Kar et al., 2013
The unfavorable desolvation effect from burying polar groups after ligand binding plays an important role in the binding event, but it is commonly neglected by most scoring functions.
“The unfavorable desolvation effect from burying polar groups after ligand binding also plays an important role in the binding event, but it is commonly neglected by most scoring functions (Kar et al., 2013; Li et al., 2014c; Cramer et al., 2017).”
From Empirical scoring functions for structure-based virtual screening: applications, critical aspects, and challenges (2018) · cites this paper as Kar et al., 2013

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Authors: Kar, P., Lipowsky, R., & Knecht, V.
Affiliations: Max Planck Institute of Colloids and Interfaces (DE)
Corresponding author: Knecht, Volker
ORCID: Kar, Parimal
Lipowsky, Reinhard
Knecht, Volker
Venue: The Journal of Physical Chemistry B
Publisher: American Chemical Society (ACS)
Published: 2013-05-08
Volume: 117
Issue: 19
Pages: 5793-5805
ISSN: 1520-5207 (ISSN-L)
1520-6106
DOI: 10.1021/jp3085292
OpenAlex: W2083946713
Cited by: 53
References: 66
Citations by year: 2026: 1 · 2025: 5 · 2024: 2 · 2023: 3 · 2022: 5 · 2021: 12 · 2020: 9 · 2019: 6 · 2018: 3 · 2017: 1 · 2016: 1 · 2015: 1 · 2014: 3 · 2013: 1
FWCI: 2.19
Type: journal article
Language: en
Open access: closed
Locations: The Journal of Physical Chemistry B (publishedVersion)
PubMed (publishedVersion)
Max Planck Institute for Plasma Physics (submittedVersion)
Max Planck Digital Library (submittedVersion)
MPG.PuRe (Max Planck Society) (submittedVersion)
Topics: Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords: HIV-1 protease inhibitors, configurational entropy, drug resistance, binding free energy decomposition, MM-PBSA, darunavir, antiretroviral drug design
MeSH terms: Mutation, Protein Conformation, Protons, Solvents, Drug Design, HIV Protease, HIV Protease Inhibitors, Entropy, Molecular Dynamics Simulation

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Importance of polar solvation and configurational entropy for design of antiretroviral drugs targeting HIV-1 protease.

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