Binding Preferences of Hydroxamate Inhibitors of the Matrix Metalloproteinase Human Fibroblast Collagenase

Toba, Samuel; Damodaran, Komath; Merz, Kenneth M.

doi:10.1021/jm980577f

Cited by 42 publications

(40 citation statements)

References 41 publications

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“…When zinc ion adopted tetrahedral geometry with coordination to three histidine nitrogens and hydroxide oxygen, the partial charges on zinc ion from MNDO calculations is +0.688|e|. In Toba's work, 35 when catalytic zinc center adopt a trigonal-bipyramidal coordination sphere, the point charge on zinc ion is about +0.80|e|. In Ryde's work, 42 the zinc charge varied by only (0.1|e| for four-and five-coordinate systems with the same basis sets, and the partial charge determined for zinc ion is +0.488|e|.…”

Section: Resultsmentioning

confidence: 98%

Binding Affinities for a Series of Selective Inhibitors of Gelatinase-A Using Molecular Dynamics with a Linear Interaction Energy Approach

Hou

Zhang

2001

J. Phys. Chem. B

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The binding of a series of hydroxamate inhibitors with gelatinase-A is examined to evaluate the viability of calculating free energies of binding, ∆G b , utilizing molecular dynamics (MD) simulations with a linear interaction energy approach. In our simulations, a bonded model was used to represent the potentials of the catalytic zinc center. The electrostatic distribution of this model was derived using a two-stage electrostatic potential fitting calculations. The resulting bonded model was then used to generate the MD trajectories. Coulombic, van der Waals, and coordinate bond energy components determined from MD simulations of the bound and unbound inhibitors solvated in water were correlated with the free energies of binding for the 15 hydroxamate inhibitors. In the correlation process, several linear models consisted of different energy components were tested. We found that besides the usually used Coulombic and van der Waals energy terms, the introduction of a constant term could significantly improve the correlation. The best model yields an average error of 0.6 kcal/mol for the 15 binding affinities, which cover an observed range of 7.2 kcal/mol. The predictive ability of the best model was revealed by the high value of q 2 (0.854) from the leave-one-out cross-validation. To this series of inhibitors, the constant term can be treated as effective adjustment to the entropy contribution in the binding free energies. The MD simulations predicted the binding mode of the gelatinase-A with the studied inhibitors, and also provided insights into the interactions occurring in the active site and the origins of variations in ∆G b . The P 1 ′ groups of inhibitors make extensive van der Waals and hydrophobic contacts with the nonpolar side chains of four residues in the S1′ subsite, including Leu 197, Val 198, Leu 218, and Tyr 223, which directly influence the ligand binding. Hydrogen bonds between hydroxamates and gelatinase-A are very important to stabilize the inhibitors in the active site. The hydrogen bonds between the P 3 ′ group and gelatinase-A can produce more favorable electrostatic interactions.

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Section: Resultsmentioning

confidence: 98%

Binding Affinities for a Series of Selective Inhibitors of Gelatinase-A Using Molecular Dynamics with a Linear Interaction Energy Approach

Hou

Zhang

2001

J. Phys. Chem. B

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“…In particular, Hoops et al selected the human carbonic anhydrase II metalloprotein (HCAII) and, using MNDO calculations, found a point charge of +0.688|e| for a zinc ion coordinated to three his- tidine nitrogen atoms and an hydroxide oxygen atom with a tetrahedral geometry [42]. In Toba's work, when catalytic zinc center adopt a trigonal-bipyramidal coordination sphere, the point charge on zinc ion is about +0.80|e| [43]. Hou et al, using analogous two-stage electrostatic potential fitting calculations with a bonded model, calculated a point charge for the five-coordinated zinc of +0.5493|e| [44].…”

Section: Model Building Partial Charge Calculation and Force Field mentioning

confidence: 99%

A modeling study of αB-crystallin in complex with zinc for seeking of correlations between chaperone-like activity and exposure of hydrophobic surfaces

Coi¹,

Bianucci²,

Ganadu³

et al. 2005

International Journal of Biological Macromolecules

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“…9) is a known hydroxamatecontaining inhibitor of several metallo hydrolases and earlier described as an aminopeptidase inhibitor. The hydroxamatecontaining compounds are very potent inhibitors of metallo enzymes, especially MMPs [137][138][139]. Although several different chelating groups have been reported in the literature, hydroxamate remains the preferred group.…”

Section: Peptide Deformilase (Pdf)mentioning

confidence: 99%

Hydroxamic Acids as Pharmacological Agents

Muri¹,

Nieto²,

Sindelar³

et al. 2002

CMC

224

149

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A variety of hydroxamic acid derivatives have recently been touted for their potential use as inhibitors of hypertension, tumor growth, inflammation, infectious agents, asthma, arthritis, and more. Here we provide a comprehensive review of the basic medicinal chemistry and pharmacology of hydroxamic acid derivatives that have been examined as inhibitors of zinc metalloproteases, matrix metalloproteinases, leukotriene A(4) hydrolases, ureases, lipoxigenases, cyclooxygenases, as well as peptide deformilases.

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Binding Preferences of Hydroxamate Inhibitors of the Matrix Metalloproteinase Human Fibroblast Collagenase

Cited by 42 publications

References 41 publications

Binding Affinities for a Series of Selective Inhibitors of Gelatinase-A Using Molecular Dynamics with a Linear Interaction Energy Approach

Binding Affinities for a Series of Selective Inhibitors of Gelatinase-A Using Molecular Dynamics with a Linear Interaction Energy Approach

A modeling study of αB-crystallin in complex with zinc for seeking of correlations between chaperone-like activity and exposure of hydrophobic surfaces

Hydroxamic Acids as Pharmacological Agents

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