24 research outputs found
IDENTIFICATION OF DRUG-LIKE MOLECULES AGAINST MATRIX METALLO PROTEINASE-13 HEMOPEXIN DOMAIN
No full textPh.DDOCTOR OF PHILOSOPH
Abstract A8: Identification of novel drug targets against MMP-13 involved in breast cancer
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Cheminformatics-Based Drug Design Approach for Identification of Inhibitors Targeting the Characteristic Residues of MMP-13 Hemopexin Domain
No full textBackground:
MMP-13, a zinc dependent protease which catalyses the cleavage of type II collagen, is expressed in osteoarthritis (OA) and rheumatoid arthritis (RA) patients, but not in normal adult tissues. Therefore, the protease has been intensively studied as a target for the inhibition of progression of OA and RA. Recent reports suggest that selective inhibition of MMP-13 may be achieved by targeting the hemopexin (Hpx) domain of the protease, which is critical for substrate specificity. In this study, we applied a cheminformatics-based drug design approach for the identification and characterization of inhibitors targeting the amino acid residues characteristic to Hpx domain of MMP-13; these inhibitors may potentially be employed in the treatment of OA and RA.
Methodology/Principal Findings:
Sequence-based mutual information analysis revealed five characteristic (completely conserved and unique), putative functional residues of the Hpx domain of MMP-13 (these residues hereafter are referred to as HCR-13pf). Binding of a ligand to as many of the HCR-13pf is postulated to result in an increased selective inhibition of the Hpx domain of MMP-13. Through the in silico structure-based high-throughput virtual screening (HTVS) method of Glide, against a large public library of 16908 molecules from Maybridge, PubChem and Binding, we identified 25 ligands that interact with at least one of the HCR-13pf. Assessment of cross-reactivity of the 25 ligands with MMP-1 and MMP-8, members of the collagenase family as MMP-13, returned seven lead molecules that did not bind to any one of the putative functional residues of Hpx domain of MMP-1 and any of the catalytic active site residues of MMP-1 and -8, suggesting that the ligands are not likely to interact with the functional or catalytic residues of other MMPs. Further, in silico analysis of physicochemical and pharmacokinetic parameters based on Lipinski's rule of five and ADMET (absorption, distribution, metabolism, excretion and toxicity) respectively, suggested potential utility of the compounds as drug leads.
Conclusions/Significance:
We have identified seven distinct drug-like molecules binding to the HCR-13pf of MMP-13 with no observable cross-reactivity to MMP-1 and MMP-8. These molecules are potential selective inhibitors of MMP-13 that can be experimentally validated and their backbone structural scaffold could serve as building blocks in designing drug-like molecules for OA, RA and other inflammatory disorders. The systematic cheminformatics-based drug design approach applied herein can be used for rational search of other public/commercial combinatorial libraries for more potent molecules, capable of selectively inhibiting the collagenolytic activity of MMP-13.Lee Foundation (Singapore
Conserved functional residues of ADCs that bind to substrate.
No full text<p>(<b>a</b>) Stereo view of structural superimposition of processed MtbADC (blue), processed <i>Thermus thermophilus</i> ADC complexed with substrate analog fumarate (red and PDB id: 2EEO) and <i>Helicobacter pylori</i> ADC complexed with substrate analog isoasparagine (green, PDB id: 1UHE). The conserved and interacting residues are labeled according to MtbADC and the interactions are shown as dashed lines. (<b>b</b>) Stereo view of the active site in the dimer interface. The figure was prepared using Molscript <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0033521#pone.0033521-Kraulis1" target="_blank">[36]</a> and Raster3D <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0033521#pone.0033521-Merritt1" target="_blank">[37]</a>.</p
Imperatorin a furocoumarin inhibits periplasmic Cu-Zn SOD of Shigella dysenteriae their by modulates its resistance towards phagocytosis during host pathogen interaction
No full textBinding poses of the identified eight lead molecules with MtbADC.
No full text<p>The binding modes of the proposed lead molecules are shown as ball and stick. Atoms colors are: H: white, C: green, N: blue, O: red and S: yellow. The interacting MtbADC residues are drawn as thin wireframe in the same color scheme and are labeled. Hydrogen bond interactions are shown as dotted yellow lines, along with the distance between donor and acceptor atoms. The binding pose of protein:lead molecule interactions were generated with the Maestro program in the Schrodinger software suite.</p
Assessment of drug-like properties of the lead molecules and fumarate as verified by Qikprop (Schrodinger 9.0).
No full texta<p>Ligand IDs are of the Maybridge, NCI, FDA ligand databases.</p>b<p>Molecular weight (<500 Da).</p>c<p>Hydrogen bond donors (<5).</p>d<p>Hydrogen bond acceptors (<10).</p>e<p>Predicted octanol/water partition co-efficient log p (recommended range: −2.0 to 6.5).</p>f<p>Predicted aqueous solubility; S in mol/L (acceptable range: −6.5 to 0.5).</p>g<p>Predicted IC<sub>50</sub> value for blockage of HERG K+ channels (acceptable range: above −5.0).</p>h<p>Predicted Caco-2 cell permeability in nm/s (acceptable range: 25 is poor and .500 is great).</p>i<p>Percentage of human oral absorption (<25% is poor and >80% is high).</p>j<p>Prediction of binding to human serum albumin (acceptable range: −1.5 to 1.5).</p
Glide extra-precision (XP) results for the eight lead molecules and fumarate by Schrodinger 9.0.
No full texta<p>The ids of the lead molecules.</p>b<p>Glide extra precision scores (kcal/mol).</p>c<p>The residues interacting with the lead molecules. The value in bracket represents the hydrogen bond distance between the atoms of respective residues, in angstrom (A°).</p>d<p>H represents the number of hydrogen bond.</p>e<p>The ligand belong to the corresponding chemical database.</p
Homology modeling and in silico screening of inhibitors for the substrate binding domain of human Siah2: implications for hypoxia-induced cancers
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