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165 a.a.
_CA
_ZN
Key reference
DOI no: 10.1021/jm980631s J Med Chem 42:1908-1920 (1999) PubMed id: 10354399
Quantitative structure-activity relationship of human neutrophil collagenase (MMP-8) inhibitors using comparative molecular field analysis and X-ray structure analysis. H.Matter, W.Schwab, D.Barbier, G.Billen, B.Haase, B.Neises, M.Schudok, W.Thorwart, H.Schreuder, V.Brachvogel, P.Lönze, K.U.Weithmann. ABSTRACT
A set of 90 novel 2-(arylsulfonyl)-1,2,3, 4-tetrahydroisoquinoline-3-carboxylates and -hydroxamates as inhibitors of the matrix metalloproteinase human neutrophil collagenase (MMP-8) was designed, synthesized, and investigated by 3D-QSAR techniques (CoMFA, CoMSIA) and X-ray structure analysis. Docking studies of a reference compound are based on crystal structures of MMP-8 complexed with peptidic inhibitors to propose a model of its bioactive conformation. This model was validated by a 1. 7 A X-ray structure of the catalytic domain of MMP-8. The 3D-QSAR models based on a superposition rule derived from these docking studies were validated using conventional and cross-validated r2 values using the leave-one-out method, repeated analyses using two randomly chosen cross-validation groups plus randomization of biological activities. This led to consistent and highly predictive 3D-QSAR models with good correlation coefficients for both CoMFA and CoMSIA, which were found to correspond to experimentally determined MMP-8 catalytic site topology in terms of steric, electrostatic, and hydrophobic complementarity. Subsets selected as smaller training sets using 2D fingerprints and maximum dissimilarity methods resulted in 3D-QSAR models with remarkable correlation coefficients and a high predictive power. This allowed to compensate the weaker zinc binding properties of carboxylates by introducing optimal fitting P1' residues. The final QSAR information agrees with all experimental data for the binding topology and thus provides clear guidelines and accurate activity predictions for novel MMP-8 inhibitors.
Literature references that cite this PDB file's key reference
PubMed id Reference
17163561 F.E.Jacobsen, J.A.Lewis, and S.M.Cohen (2007).
The Design of Inhibitors for Medicinally Relevant Metalloproteins.ChemMedChem, 2, 152-171.
15185333 D.Jung, J.Floyd, and T.M.Gund (2004).
A comparative molecular field analysis (CoMFA) study using semiempirical, density functional, ab initio methods and pharmacophore derivation using DISCOtech on sigma 1 ligands.J Comput Chem, 25, 1385-1399.
14732707 V.Lukacova, Y.Zhang, M.Mackov, P.Baricic, S.Raha, J.A.Calvo, and S.Balaz (2004).
Similarity of binding sites of human matrix metalloproteinases.J Biol Chem, 279, 14194-14200.
14532275 H.I.Park, Y.Jin, D.R.Hurst, C.A.Monroe, S.Lee, M.A.Schwartz, and Q.X.Sang (2003).
The intermediate S1' pocket of the endometase/matrilysin-2 active site revealed by enzyme inhibition kinetic studies, protein sequence analyses, and homology modeling.J Biol Chem, 278, 51646-51653.
12119297 H.I.Park, B.E.Turk, F.E.Gerkema, L.C.Cantley, and Q.X.Sang (2002).
Peptide substrate specificities and protein cleavage sites of human endometase/matrilysin-2/matrix metalloproteinase-26.J Biol Chem, 277, 35168-35175.
11054124 D.S.Yang, J.McLaurin, K.Qin, D.Westaway, and P.E.Fraser (2000).
Examining the zinc binding site of the amyloid-beta peptide.Eur J Biochem, 267, 6692-6698. The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time.
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