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

2004 ◽  
Vol 47 (27) ◽  
pp. 6673-6680 ◽  
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

scholarly journals 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

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>

scholarly journals 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

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>

scholarly journals Novel Protease Inhibitors (PIs) Containing Macrocyclic Components and 3(R),3a(S),6a(R)-bis-Tetrahydrofuranylurethane That Are Potent against Multi-PI-Resistant HIV-1 Variants In Vitro

2010 ◽  
Vol 54 (8) ◽  
pp. 3460-3470 ◽  
Author(s):  
Yasushi Tojo ◽  
Yasuhiro Koh ◽  
Masayuki Amano ◽  
Manabu Aoki ◽  
Debananda Das ◽  
...  
Keyword(s):  
Protease Inhibitors ◽  
Molecular Design ◽  
Antiviral Agent ◽  
Structural Features ◽  
Biological Properties ◽  
Van Der Waals Interactions ◽  
Protein Ligand Interactions ◽  
Ligand Interactions ◽  
Hiv 1

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 .

scholarly journals Probing Multidrug-Resistance and Protein-Ligand Interactions with Oxatricyclic Designed Ligands in HIV-1 Protease Inhibitors

ChemMedChem ◽  
2010 ◽  
Vol 5 (11) ◽  
pp. 1850-1854 ◽  
Author(s):  
Arun K. Ghosh ◽  
Chun-Xiao Xu ◽  
Kalapala Venkateswara Rao ◽  
Abigail Baldridge ◽  
Johnson Agniswamy ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Protease Inhibitors ◽  
Protein Ligand Interactions ◽  
Ligand Interactions ◽  
Hiv 1

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

2003 ◽  
Vol 77 (2) ◽  
pp. 1306-1315 ◽  
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.

scholarly journals Molecular basis for high affinity agonist binding in GPCRs

2018 ◽  
Author(s):  
Tony Warne ◽  
Patricia C. Edwards ◽  
Andrew S. Doré ◽  
Andrew G. W. Leslie ◽  
Christopher G. Tate
Keyword(s):  
Hydrogen Bonds ◽  
Binding Site ◽  
G Protein ◽  
Molecular Basis ◽  
Agonist Binding ◽  
High Affinity ◽  
Protein Ligand Interactions ◽  
Wide Range ◽  
Ligand Interactions ◽  
G Protein Coupled

AbstractA characteristic of GPCRs in the G protein-coupled state is that the affinity of the agonist often increases significantly, but the molecular basis for this is unclear. We have determined six active-state structures of the β1-adrenoceptor (β1AR) bound to conformation-specific nanobodies in the presence of agonists of varying efficacy. A direct comparison with structures of β1AR in inactive states bound to the identical ligands showed a 24-42% reduction in the volume of the orthosteric binding site. Potential hydrogen bonds were also shorter, and there was up to a 30% increase in the number of atomic contacts between the receptor and ligand. GPCRs are highly conserved, so these factors will likely be essential in increasing the affinity of a wide range of structurally distinct agonists.One Sentence SummaryHigh affinity agonist binding to G protein-coupled GPCRs results from an increase in the number and strength of protein-ligand interactions.

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

ChemMedChem ◽  
2010 ◽  
Vol 5 (11) ◽  
pp. 1797-1797
Author(s):  
Arun K. Ghosh ◽  
Chun-Xiao Xu ◽  
Kalapala Venkateswara Rao ◽  
Abigail Baldridge ◽  
Johnson Agniswamy ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Protease Inhibitors ◽  
Protein Ligand Interactions ◽  
Ligand Interactions ◽  
Hiv 1

scholarly journals Entropy in molecular recognition by proteins

2017 ◽  
Vol 114 (25) ◽  
pp. 6563-6568 ◽  
Author(s):  
José A. Caro ◽  
Kyle W. Harpole ◽  
Vignesh Kasinath ◽  
Jackwee Lim ◽  
Jeffrey Granja ◽  
...  
Keyword(s):  
Molecular Recognition ◽  
Protein Interactions ◽  
Nmr Relaxation ◽  
Quantitative Relationship ◽  
Accessible Surface Area ◽  
Conformational Entropy ◽  
General Role ◽  
High Affinity ◽  
Protein Ligand Interactions ◽  
Ligand Interactions

Molecular recognition by proteins is fundamental to molecular biology. Dissection of the thermodynamic energy terms governing protein–ligand interactions has proven difficult, with determination of entropic contributions being particularly elusive. NMR relaxation measurements have suggested that changes in protein conformational entropy can be quantitatively obtained through a dynamical proxy, but the generality of this relationship has not been shown. Twenty-eight protein–ligand complexes are used to show a quantitative relationship between measures of fast side-chain motion and the underlying conformational entropy. We find that the contribution of conformational entropy can range from favorable to unfavorable, which demonstrates the potential of this thermodynamic variable to modulate protein–ligand interactions. For about one-quarter of these complexes, the absence of conformational entropy would render the resulting affinity biologically meaningless. The dynamical proxy for conformational entropy or “entropy meter” also allows for refinement of the contributions of solvent entropy and the loss in rotational-translational entropy accompanying formation of high-affinity complexes. Furthermore, structure-based application of the approach can also provide insight into long-lived specific water–protein interactions that escape the generic treatments of solvent entropy based simply on changes in accessible surface area. These results provide a comprehensive and unified view of the general role of entropy in high-affinity molecular recognition by proteins.

scholarly journals 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 ◽  
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.

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