Design and synthesis of the cartilage protective agent (CPA, Ro32-3555)

Broadhurst, Michael J.; Brown, Paul A.; Lawton, Geoffrey; Ballantyne, N.; Borkakoti, Neera; Bottomley, K. M. K.; Cooper, Mark; Eatherton, Andrew J.; Kilford, Ian R.; Malsher, P.J.; Nixon, John; Lewis, E. J.; Sutton, Blaine M.; Johnson, William H.

doi:10.1016/s0960-894x(97)00416-2

Cited by 44 publications

(23 citation statements)

References 11 publications

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“…[38][39][40] The studied compounds are shown in Table 1. The construction of the complex structure of proMMP-2 with the studied molecules could be divided into three stages.…”

Section: Methods and Computational Detailsmentioning

confidence: 99%

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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“…[38][39][40] The studied compounds are shown in Table 1. The construction of the complex structure of proMMP-2 with the studied molecules could be divided into three stages.…”

Section: Methods and Computational Detailsmentioning

confidence: 99%

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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“…This type of design culminated with British Biotech's achievement in putting forth two succinate hydroxamate peptidomimetics into clinical trials, batimastat (1) and marimastat (2). These two first generation inhibitors exhibit a broad-spectrum MMP Truncation of the P 2´ -P 3´ group of pseudopeptidic succinyl hydroxamic acid derivatives has culminated in the discovery of Trocade (5; Ro 32-3555), which was in phase III clinical trials for rheumatoid arthritis until recently [122]. Trocade exhibits an oral bioavailability of 26% in the rat and inhibits articular cartilage degradation in a rat monoarthritis model.…”

Section: Small Molecule Inhibitors Of Mmpsmentioning

confidence: 99%

The Design, Structure, and Therapeutic Application of Matrix Metalloproteinase Inhibitors

Skiles¹,

Gonnella²,

Jeng³

2001

CMC

211

144

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Matrix metalloproteinases (MMPs) are a family of zinc-containing enzymes involved in the degradation and remodeling of extracellular matrix proteins. The activities of these enzymes are well regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs). Chronic stimulation of MMP activities due to an imbalance in the levels of MMPs and TIMPs has been implicated in the pathogenesis of a variety of diseases such as cancer, osteoarthritis, and rheumatoid arthritis. Thus, MMP inhibitors are expected to be useful for the treatment of these disorders. This article reviews briefly the biochemistry of MMPs and evidence for their pathogenic roles using molecular biology approaches. Biomolecular structures used in the design of MMP inhibitors are thoroughly covered. Major emphasis is on recently published potent, small molecular weight MMP inhibitors and their pharmacological properties. Finally, available clinical results of compounds in development are summarized.

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“…Early structure-activity relationship studies [25] showed that the subsites that recognize the residues N-terminal to the scissile bond are flat and ill-defined, so that compounds spanning unprimed subsites result in inhibitors with micromolar potency. Thus subsequent medicinal chemistry and structural biology efforts have been concentrated on probing enzyme-inhibitor interactions of analogues straddling the S1 -S3 subsites [26].…”

Section: Residue Requirementsmentioning

confidence: 99%

Matrix metalloprotease inhibitors: design from structure

Borkakoti

2004

Biochemical Society Transactions

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The zinc- and calcium-dependent family of proteins called the MMPs (matrix metalloproteases) are collectively responsible for the degradation of the extracellular matrix. The enzymes are synthesized as zymogens, and under physiological conditions are selectively regulated by endogenous inhibitors. An imbalance between the active enzymes and their natural inhibitors leads to the accelerated destruction of connective tissue associated with the pathology of diseases such as arthritis, cancer, multiple sclerosis and cardiovascular diseases. The potential for using specific enzyme inhibitors as therapeutic agents to redress this balance has led to intensive research focused on the design, synthesis and molecular deciphering of low-molecular-mass inhibitors of this family of proteins. The design of early MMP inhibitors was based on the scissile site sequence of peptide substrates, with moieties customized to chelate the critical zinc ion at the enzymes' active site. These initial efforts were supported by X-ray and NMR data on MMP complexes, exploiting sequence and structural differences in the principal specificity pocket of the enzymes, leading to subtype-selective MMP inhibitors. This review will provide a critical appraisal of the design principles that have been utilized in generating molecules that inhibit MMPs, and explore issues relevant to obtaining clinical efficacy of MMP inhibitor-based therapies.

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Design and synthesis of the cartilage protective agent (CPA, Ro32-3555)

Cited by 44 publications

References 11 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

The Design, Structure, and Therapeutic Application of Matrix Metalloproteinase Inhibitors

Matrix metalloprotease inhibitors: design from structure

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