Accurate prediction of relative binding affinities of a series of HIV‐1 protease inhibitors using semi‐empirical quantum mechanical charge

2020 ◽  
Vol 41 (19) ◽  
pp. 1773-1780
Author(s):  
Cheng Peng ◽  
Jinan Wang ◽  
Zhijian Xu ◽  
Tingting Cai ◽  
Weiliang Zhu
Keyword(s):  
Protease Inhibitors ◽  
Accurate Prediction ◽  
Quantum Mechanical ◽  
Binding Affinities ◽  
Relative Binding ◽  
Semi Empirical ◽  
Hiv 1 ◽  
Mechanical Charge

Computational Studies on HIV-1 Protease Inhibitors:  Influence of Calculated Inhibitor−Enzyme Binding Affinities on the Statistical Quality of 3D-QSAR CoMFA Models

2000 ◽  
Vol 43 (23) ◽  
pp. 4446-4451 ◽  
Author(s):  
Philippa R. N. Jayatilleke ◽  
Anil C. Nair ◽  
Randy Zauhar ◽  
William J. Welsh
Keyword(s):  
Protease Inhibitors ◽  
3D Qsar ◽  
Computational Studies ◽  
Binding Affinities ◽  
Statistical Quality ◽  
Enzyme Binding ◽  
Hiv 1

scholarly journals Molecular Basis for Increased Susceptibility of Isolates with Atazanavir Resistance-Conferring Substitution I50L to Other Protease Inhibitors

2005 ◽  
Vol 49 (9) ◽  
pp. 3825-3832 ◽  
Author(s):  
Joseph Yanchunas ◽  
David R. Langley ◽  
Li Tao ◽  
Ronald E. Rose ◽  
Jacques Friborg ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Protease Inhibitors ◽  
Hiv Protease ◽  
Cross Resistance ◽  
Titration Calorimetry ◽  
Binding Affinities ◽  
The Novel ◽  
Immunodeficiency Virus ◽  
Effective Drugs ◽  
Hiv 1

ABSTRACT Protease inhibitors (PIs) are highly effective drugs against the human immunodeficiency virus (HIV), yet long-term therapeutic use is limited by emergence of HIV type 1 (HIV-1) protease substitutions that confer cross-resistance to multiple protease inhibitor drugs. Atazanavir is a highly potent HIV protease inhibitor with a distinct resistance profile that includes effectiveness against most HIV-1 isolates resistant to one or two PIs. The signature resistance substitution for atazanavir is I50L, and it is frequently (53%) accompanied by a compensatory A71V substitution that helps restore viability and increases atazanavir resistance levels. We measured the binding affinities of wild-type (WT) and I50L/A71V HIV-1 proteases to atazanavir and other currently approved PIs (ritonavir, lopinavir, saquinavir, nelfinavir, indinavir, and amprenavir) by isothermal titration calorimetry. Remarkably, we find that all of the PIs have 2- to 10-fold increased affinities for I50L/A71V protease, except for atazanavir. The results are also manifested by thermal stability measures of affinity for WT and I50L/A71V proteases. Additional biophysical and enzyme kinetics experiments show I50L/A71V protease is a stable enzyme with catalytic activity that is slightly reduced (34%) relative to the WT. Computational modeling reveals that the unique resistance phenotype of I50L/A71V protease likely originates from bulky tert-butyl groups at P2 and P2′ (specific to atazanavir) that sterically clash with methyl groups on residue L50. The results of this study provide a molecular understanding of the novel hypersusceptibility of atazanavir-resistant I50L/A71V-containing clinical isolates to other currently approved PIs.

Cyclic HIV-1 Protease Inhibitors Derived from Mannitol:  Synthesis, Inhibitory Potencies, and Computational Predictions of Binding Affinities

1997 ◽  
Vol 40 (6) ◽  
pp. 885-897 ◽  
Author(s):  
Johan Hultén ◽  
Nicholas M. Bonham ◽  
Ulrika Nillroth ◽  
Tomas Hansson ◽  
Guido Zuccarello ◽  
...  
Keyword(s):  
Protease Inhibitors ◽  
Binding Affinities ◽  
Hiv 1 ◽  
Computational Predictions

Fast and accurate determination of the relative binding affinities of small compounds to HIV-1 protease using non-equilibrium work

2016 ◽  
Vol 37 (31) ◽  
pp. 2734-2742 ◽  
Author(s):  
Son Tung Ngo ◽  
Huynh Minh Hung ◽  
Minh Tho Nguyen
Keyword(s):  
Accurate Determination ◽  
Binding Affinities ◽  
Relative Binding ◽  
Hiv 1 ◽  
Non Equilibrium

Stereoisomers of Cyclic Urea HIV-1 Protease Inhibitors:  Synthesis and Binding Affinities

1998 ◽  
Vol 41 (25) ◽  
pp. 5113-5117 ◽  
Author(s):  
Robert F. Kaltenbach ◽  
David A. Nugiel ◽  
Patrick Y. S. Lam ◽  
Ronald M. Klabe ◽  
Steven P. Seitz
Keyword(s):  
Protease Inhibitors ◽  
Binding Affinities ◽  
Hiv 1

An oral high dose of cholecalciferol restores vitamin D status in deficient postmenopausal HIV-1 infected women independently of protease inhibitors therapy

2015 ◽  
Author(s):  
Jessica Pepe ◽  
Ivano Mezzaroma ◽  
Alessandra Fantauzzi ◽  
Mario Falciano ◽  
Alessandra Salotti ◽  
...  
Keyword(s):  
Vitamin D ◽  
Protease Inhibitors ◽  
High Dose ◽  
Vitamin D Status ◽  
Hiv 1

Modelling Flexible Protein-Ligand Binding in p38α MAP Kinase using the QUBE Force Field

2019 ◽  
Author(s):  
Joshua Horton ◽  
Alice Allen ◽  
Daniel Cole
Keyword(s):  
Quantum Mechanics ◽  
Force Field ◽  
Map Kinase ◽  
Binding Free Energy ◽  
Quantum Mechanical ◽  
Enhanced Sampling ◽  
Relative Binding ◽  
Stringent Test ◽  
Flexible Protein ◽  
P38α Map Kinase

<div><div><div><p>The quantum mechanical bespoke (QUBE) force field is used to retrospectively calculate the relative binding free energy of a series of 17 flexible inhibitors of p38α MAP kinase. The size and flexibility of the chosen molecules represent a stringent test of the derivation of force field parameters from quantum mechanics, and enhanced sampling is required to reduce the dependence of the results on the starting structure. Competitive accuracy with a widely-used biological force field is achieved, indicating that quantum mechanics derived force fields are approaching the accuracy required to provide guidance in prospective drug discovery campaigns.</p></div></div></div>

A convergent synthesis of the spiroketal moiety of the HIV-1 protease inhibitors didemnaketals

Tetrahedron ◽  
2002 ◽  
Vol 58 (9) ◽  
pp. 1697-1708 ◽  
Author(s):  
Yan Xing Jia ◽  
Xin Li ◽  
Bin Wu ◽  
Xue Zhi Zhao ◽  
Yong Qiang Tu
Keyword(s):  
Protease Inhibitors ◽  
Convergent Synthesis ◽  
Hiv 1
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