Cover Picture: Probing Multidrug-Resistance and Protein-Ligand Interactions with Oxatricyclic Designed Ligands in HIV-1 Protease Inhibitors (ChemMedChem 11/2010)

ABSTRACT Natural products with macrocyclic structural features often display intriguing biological properties. Molecular design incorporating macrocycles may lead to molecules with unique protein-ligand interactions. We generated novel human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) containing a macrocycle and bis-tetrahydrofuranylurethane. Four such compounds exerted potent activity against HIV-1LAI and had 50% effective concentrations (EC50s) of as low as 0.002 μM with minimal cytotoxicity. GRL-216 and GRL-286 blocked the replication of HIV-1NL4-3 variants selected by up to 5 μM saquinavir, ritonavir, nelfinavir, lopinavir, or atazanavir; they had EC50s of 0.020 to 0.046 μM and potent activities against six multi-PI-resistant clinical HIV-1 (HIVmPIr ) variants with EC50s of 0.027 to 0.089 μM. GRL-216 and -286 also blocked HIV-1 protease dimerization as efficiently as darunavir. When HIV-1NL4-3 was selected by GRL-216, it replicated progressively more poorly and failed to replicate in the presence of >0.26 μM GRL-216, suggesting that the emergence of GRL-216-resistant HIV-1 variants is substantially delayed. At passage 50 with GRL-216 (the HIV isolate selected with GRL-216 at up to 0.16 μM [HIV216-0.16 μM]), HIV-1NL4-3 containing the L10I, L24I, M46L, V82I, and I84V mutations remained relatively sensitive to PIs, including darunavir, with the EC50s being 3- to 8-fold-greater than the EC50 of each drug for HIV-1NL4-3. Interestingly, HIV216-0.16 μM had 10-fold increased sensitivity to tipranavir. Analysis of the protein-ligand X-ray structures of GRL-216 revealed that the macrocycle occupied a greater volume of the binding cavity of protease and formed greater van der Waals interactions with V82 and I84 than darunavir. The present data warrant the further development of GRL-216 as a potential antiviral agent for treating individuals harboring wild-type and/or HIVmPIr .

Download Full-text

Multidrug resistance reversal properties and cytotoxic evaluation of representatives of a novel class of HIV-1 protease inhibitors

Journal of Pharmacy and Pharmacology ◽

10.1111/j.2042-7158.2010.01144.x ◽

2010 ◽

Vol 62 (12) ◽

pp. 1704-1710 ◽

Cited By ~ 5

Author(s):

Claudius Coburger ◽

Hermann Lage ◽

Joséf Molnár ◽

Andreas Langner ◽

Andreas Hilgeroth

Keyword(s):

Multidrug Resistance ◽

Protease Inhibitors ◽

Resistance Reversal ◽

Hiv 1

Download Full-text

A Combined QM/MM Approach to Protein−Ligand Interactions: Polarization Effects of the HIV-1 Protease on Selected High Affinity Inhibitors

Journal of Medicinal Chemistry ◽

10.1021/jm0497343 ◽

2004 ◽

Vol 47 (27) ◽

pp. 6673-6680 ◽

Cited By ~ 83

Author(s):

Christian Hensen ◽

Johannes C. Hermann ◽

Kwangho Nam ◽

Shuhua Ma ◽

Jiali Gao ◽

...

Keyword(s):

Polarization Effects ◽

High Affinity ◽

Protein Ligand Interactions ◽

Ligand Interactions ◽

Hiv 1

Download Full-text

Combining Molecular Dynamic Information and an Aspherical-Atom Data Bank in the Evaluation of the Electrostatic Interaction Energy in Multimeric Protein-Ligand Complex: A Case Study for HIV-1 Protease

10.26434/chemrxiv.13513161 ◽

2021 ◽

Author(s):

Prashant Kumar ◽

Paulina Dominiak

Keyword(s):

Interaction Energy ◽

Molecular Dynamic ◽

Binding Affinity ◽

Electrostatic Interaction ◽

Electrostatic Interactions ◽

Data Bank ◽

Scoring Functions ◽

Protein Ligand Interactions ◽

Ligand Interactions ◽

Hiv 1

<div> <div> <div> <p>Computational analysis of protein-ligand interactions is of crucial importance for drug discovery. Assessment of ligand binding energy allows us to have a glimpse on the potential of a small organic molecule to be a ligand to the binding site of a protein target. Available scoring functions such as in docking programs, we could say that they all rely on equations that sum each type of protein-ligand interactions to model the binding affinity. Most of the scoring functions consider electrostatic interactions involving the protein and the ligand. Electrostatic interactions contribute one of the most important part of total interaction energies between macromolecules, unlike dispersion forces they are highly directional and therefore dominate the nature of molecular packing in crystals and in biological complexes and contribute significantly to differences in inhibition strength among related enzyme inhibitors. In this paper, complexes of HIV-1 protease with inhibitor molecules (JE-2147 and Darunavir) have been analysed using charge densities from a transferable aspherical-atom data bank. Moreover, we analyse the electrostatic interaction energy for an ensemble of structures using molecular dynamic simulation to highlight the main features related to the importance of this interaction for binding affinity. </p> </div> </div> </div>

Download Full-text

Combining Molecular Dynamic Information and an Aspherical-Atom Data Bank in the Evaluation of the Electrostatic Interaction Energy in Multimeric Protein-Ligand Complex: A Case Study for HIV-1 Protease

10.26434/chemrxiv.13513161.v1 ◽

2021 ◽

Author(s):

Prashant Kumar ◽

Paulina Dominiak

Keyword(s):

Interaction Energy ◽

Molecular Dynamic ◽

Binding Affinity ◽

Electrostatic Interaction ◽

Electrostatic Interactions ◽

Data Bank ◽

Scoring Functions ◽

Protein Ligand Interactions ◽

Ligand Interactions ◽

Hiv 1

<div> <div> <div> <p>Computational analysis of protein-ligand interactions is of crucial importance for drug discovery. Assessment of ligand binding energy allows us to have a glimpse on the potential of a small organic molecule to be a ligand to the binding site of a protein target. Available scoring functions such as in docking programs, we could say that they all rely on equations that sum each type of protein-ligand interactions to model the binding affinity. Most of the scoring functions consider electrostatic interactions involving the protein and the ligand. Electrostatic interactions contribute one of the most important part of total interaction energies between macromolecules, unlike dispersion forces they are highly directional and therefore dominate the nature of molecular packing in crystals and in biological complexes and contribute significantly to differences in inhibition strength among related enzyme inhibitors. In this paper, complexes of HIV-1 protease with inhibitor molecules (JE-2147 and Darunavir) have been analysed using charge densities from a transferable aspherical-atom data bank. Moreover, we analyse the electrostatic interaction energy for an ensemble of structures using molecular dynamic simulation to highlight the main features related to the importance of this interaction for binding affinity. </p> </div> </div> </div>

Download Full-text

Viability of a Drug-Resistant Human Immunodeficiency Virus Type 1 Protease Variant: Structural Insights for Better Antiviral Therapy

Journal of Virology ◽

10.1128/jvi.77.2.1306-1315.2003 ◽

2003 ◽

Vol 77 (2) ◽

pp. 1306-1315 ◽

Cited By ~ 61

Author(s):

Moses Prabu-Jeyabalan ◽

Ellen A. Nalivaika ◽

Nancy M. King ◽

Celia A. Schiffer

Keyword(s):

Human Immunodeficiency Virus ◽

Resistant Mutant ◽

Drug Resistant ◽

Protein Ligand Interactions ◽

Immunodeficiency Virus ◽

Ligand Interactions ◽

Drug Resistant Mutant ◽

Structural Insights ◽

Hiv 1

ABSTRACT Under the selective pressure of protease inhibitor therapy, patients infected with human immunodeficiency virus (HIV) often develop drug-resistant HIV strains. One of the first drug-resistant mutations to arise in the protease, particularly in patients receiving indinavir or ritonavir treatment, is V82A, which compromises the binding of these and other inhibitors but allows the virus to remain viable. To probe this drug resistance, we solved the crystal structures of three natural substrates and two commercial drugs in complex with an inactive drug-resistant mutant (D25N/V82A) HIV-1 protease. Through structural analysis and comparison of the protein-ligand interactions, we found that Val82 interacts more closely with the drugs than with the natural substrate peptides. The V82A mutation compromises these interactions with the drugs while not greatly affecting the substrate interactions, which is consistent with previously published kinetic data. Coupled with our earlier observations, these findings suggest that future inhibitor design may reduce the probability of the appearance of drug-resistant mutations by targeting residues that are essential for substrate recognition.

Download Full-text

Combining Molecular Dynamic Information and an Aspherical-Atom Data Bank in the Evaluation of the Electrostatic Interaction Energy in Multimeric Protein-Ligand Complex: A Case Study for HIV-1 Protease

Molecules ◽

10.3390/molecules26133872 ◽

2021 ◽

Vol 26 (13) ◽

pp. 3872

Author(s):

Prashant Kumar ◽

Paulina Maria Dominiak

Keyword(s):

Interaction Energy ◽

Molecular Dynamic ◽

Binding Affinity ◽

Electrostatic Interaction ◽

Electrostatic Interactions ◽

Scoring Functions ◽

Ligand Complex ◽

Protein Ligand Interactions ◽

Ligand Interactions ◽

Hiv 1

Computational analysis of protein–ligand interactions is of crucial importance for drug discovery. Assessment of ligand binding energy allows us to have a glimpse of the potential of a small organic molecule to be a ligand to the binding site of a protein target. Available scoring functions, such as in docking programs, all rely on equations that sum each type of protein–ligand interactions in order to predict the binding affinity. Most of the scoring functions consider electrostatic interactions involving the protein and the ligand. Electrostatic interactions constitute one of the most important part of total interactions between macromolecules. Unlike dispersion forces, they are highly directional and therefore dominate the nature of molecular packing in crystals and in biological complexes and contribute significantly to differences in inhibition strength among related enzyme inhibitors. In this study, complexes of HIV-1 protease with inhibitor molecules (JE-2147 and darunavir) were analyzed by using charge densities from the transferable aspherical-atom University at Buffalo Databank (UBDB). Moreover, we analyzed the electrostatic interaction energy for an ensemble of structures, using molecular dynamic simulations to highlight the main features of electrostatic interactions important for binding affinity.

Download Full-text