Determination of the relative binding free energies of peptide inhibitors to the HIV-1 protease

Ferguson, David M.; Radmer, Randall J.; Kollman, Peter A.

doi:10.1021/jm00112a048

Cited by 79 publications

(54 citation statements)

References 2 publications

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“…lyze which of the two diastereoisomers, R or S in the HEA -OH group, binds better to the active site of HIV protease. It was calculated that the S stereoisomer binds better by 24 kcal/mol than the R isomer [5,6], in good agreement with concurrent experiments which suggest a AAG (R vs. S) of comparable magnitude [7].…”

Section: Introductionsupporting

confidence: 79%

Peptide mimetics as enzyme inhibitors: Use of free energy perturbation calculations to evaluate isosteric replacement for amide bonds in a potent HIV protease inhibitor

Cieplak

Kollman

1993

J Computer-Aided Mol Des

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We present the application of free energy perturbation theory/molecular dynamics to predict the consequence of replacing each of the seven peptide bonds in the potent HIV protease inhibitor JG365: ACE (acetyl)-Ser-Leu-Asn-HEA (hydroxyethylamine analog of Phe-Pro)-Ile-Val-NME (N-methyl) by ethylene or fluoroethylene isosteres. Replacing two of these bonds may well lead to significantly tighter binding; replacing two others is predicted to significantly diminish the binding affinity. Also, for three of the peptide bonds fluoroethylene replacements could lead to increased binding of free energies of the inhibitors. Our results should be considered as predictive since there are, as yet, no experimental results on such peptide replacements as enzyme inhibitors.

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Section: Introductionsupporting

confidence: 79%

Peptide mimetics as enzyme inhibitors: Use of free energy perturbation calculations to evaluate isosteric replacement for amide bonds in a potent HIV protease inhibitor

Cieplak

Kollman

1993

J Computer-Aided Mol Des

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“…8 The most accurate computational method for estimating relative binding affinities of structurally similar inhibitors to an enzyme is the free energy perturbation (FEP) approach using with either molecular dynamics (MD) or Monte Carlo (MC) simulations. 9 Despite its high accuracy, free energy calculations have primarily been used to rationalize experimentally determined binding affinities [10][11][12][13][14] with few applications focusing on predictions. [15][16][17][18] This article presents our efforts to utilize computer-aided drug design approaches, particularly, FEP method for estimating relative binding affinities for five pairs of mutant and wild-type structures of the FBPase:AMP complex and compare the free energy results with experimentally determined binding affinities.…”

Section: Introductionmentioning

confidence: 99%

Calculation of relative binding affinities of fructose 1,6‐bisphosphatase mutants with adenosine monophosphate using free energy perturbation method

Mutyala¹,

Reddy²,

Sumakanth³

et al. 2007

J Comput Chem

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The free energy perturbation (FEP) methodology is the most accurate means of estimating relative binding affinities between inhibitors and protein variants. In this article, the importance of hydrophobic and hydrophilic residues to the binding of adenosine monophosphate (AMP) to the fructose 1,6-bisphosphatase (FBPase), a target enzyme for type-II diabetes, was examined by FEP method. Five mutations were made to the FBPase enzyme with AMP inhibitor bound: 113Tyr --> 113Phe, 31Thr --> 31Ala, 31Thr --> 31Ser, 177Met --> 177Ala, and 30Leu --> 30Phe. These mutations test the strength of hydrogen bonds and van der Waals interactions between the ligand and enzyme. The calculated relative free energies indicated that: 113Tyr and 31Thr play an important role, each via two hydrogen bonds affecting the binding affinity of inhibitor AMP to FBPase, and any changes in these hydrogen bonds due to mutations on the protein will have significant effect on the binding affinity of AMP to FBPase, consistent to experimental results. Also, the free energy calculations clearly show that the hydrophilic interactions are more important than the hydrophobic interactions of the binding pocket of FBPase.

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“…[6][7] A free energy simulation technique known as the thermodynamic cycle perturbation (TCP) approach [8][9][10][11] used in conjunction with molecular dynamics calculations offers a theoretically precise method of determining the binding free energy differences of structurally related inhibitors. Despite its high accuracy, free energy calculations [12][13][14][15][16][17] have primarily been used to rationalize experimentally determined binding affinities rather than predict affinities of new analogues. The reluctance to use free energy calculations for predictions and therefore drug design is partly § Member of Translational Research Center for Protein Function Control, Korea.…”

Section: Introductionmentioning

confidence: 99%

Prediction of Relative Stability between TACE/Gelastatin and TACE/Gelastatin Hydroxamate

Nam¹,

Han²,

Kim³

et al. 2010

Bulletin of the Korean Chemical Society

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A gelastatins (1), natural MMP inhibitors, and their hydroxamate analogues (2) in TACE enzyme evaluated for discovery of potent TACE inhibitors. We have employed molecular dynamics simulations to compute the relative free energy of hydration and binding to TACE for gelastatin (1) and its hydroxamate analogue (2). The relative free energy difference is directly described in this article using the free energy perturbation approach as a means to accurately predict the TACE inhibitor of gelastatin analogues. The results show that the good agreement between the experimental and theoretical relative free energies of binding, gelastatin hydroxamate (2) binds stronger to TACE by -3.37 kcal/mol. The desolvation energy costs significantly reduced binding affinity, hydroxamate group associated with high desolvation energy formed strong favorable interactions with TACE with more than compensated for the solvation costs and therefore led to an improvement in relative binding affinity.

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Determination of the relative binding free energies of peptide inhibitors to the HIV-1 protease

Cited by 79 publications

References 2 publications

Peptide mimetics as enzyme inhibitors: Use of free energy perturbation calculations to evaluate isosteric replacement for amide bonds in a potent HIV protease inhibitor

Peptide mimetics as enzyme inhibitors: Use of free energy perturbation calculations to evaluate isosteric replacement for amide bonds in a potent HIV protease inhibitor

Calculation of relative binding affinities of fructose 1,6‐bisphosphatase mutants with adenosine monophosphate using free energy perturbation method

Prediction of Relative Stability between TACE/Gelastatin and TACE/Gelastatin Hydroxamate

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