233 research outputs found
Cheminformatics-Based Drug Design Approach for Identification of Inhibitors Targeting the Characteristic Residues of MMP-13 Hemopexin Domain
Get PDFBackground:
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
Dataset of "Vertical pathway inhibition of receptor tyrosine kinases and BAD with synergistic efficacy in triple negative breast cancer"
No full textStructure, dielectric, thermal and I-V studies of electron beam irradiated PVDF-HFP/LiClO4 electrolyte film
No full textEnhanced optical and electrochemical properties of polyaniline/cobalt oxide nano composite
No full textComparative analysis of Bootan's and Axelby's describing functions
No full textLinearization of nonlinear systems with random inputs using the describing function technique is discussed. Using Bootan's and Axelby's definitions the expressions for the equivalent describing function K[subscript n] for several types of nonlinearities are derived and the difference in the values of K[subscript n] which result from the two approaches is illustrated. A particular nonlinearity combined with a third order linear system is considered for analysis using both definition of K[subscript n]. The discrepancies that arise in the design or analysis of a control system using the two definitions is clearly presented and the for this nonlinearity that provides the best approximation of the actual system behavior is determined by simulating the physical model on an analog computer.Electrical and Computer Engineering, Department o
TFF3 facilitates dormancy of anti-estrogen treated ER+ mammary carcinoma
No full textBackground: Tumor dormancy is a substantial clinical obstacle in treatment of estrogen receptor positive mammary carcinoma (ER+MC), contributing to drug resistance, metastatic outgrowth, relapse, and consequent mortality. Methods: Preclinical models mimicking clinical anti-estrogen-induced ER+MC dormancy were generated in vivo. Function and a mechanism-based combination treatment were determined in the generated dormancy-like models in vitro, ex vivo, and in vivo. Results: The dormancy models display molecular features of dormancy and tumor mass and cellular dormancy with associated clinical dormancy behavior. Both serum and cancer tissue expression of Trefoil factor 3 (TFF3) are identified as prognostic indicators of dormant ER+MC with TFF3 functioning as an epigenetically regulated driver of dormancy-associated behaviors. BCL2-dependent pro-survival functions of TFF3 coupled with enhanced attributes of stemness designates TFF3 as an actionable target. Moreover, combination screening of a TFF3 small-molecule-inhibitor (AMPC) with compounds used clinically to treat anti-estrogen-resistant ER+MC identifies strong synergism between AMPC and CDK4/6 inhibitors in the dormancy-like models. The combination results in concomitant suppression of CCND1 expression and CDK4/6 kinase activity to decrease RB phosphorylation, with reduced BCL2 expression, leading to both ER + MC cell cycle arrest and apoptosis. The combined TFF3-CDK4/6 inhibition impedes metastatic outgrowth and ameliorates host animal survival in the dormancy-like models, producing a complete response in a percentage of animals. Conclusions: Hence, in vivo models of anti-estrogen induced dormancy of ER+MC generated herein, identify TFF3 as a driver of this process. The combined inhibition of TFF3 and CDK4/6 may potentially alleviate the clinical challenges posed by anti-estrogen-induced dormancy in ER+MC. © The Author(s) 2025
Modelling multiserver systems with time or operation dependent breakdowns, alternate repair strategies, reconfiguration and rebooting delays
No full textReal-Time Implementation and Analysis of Crop-Field for Agriculture Management System based on Microcontroller with GPRS (M-GPRS) and SMS
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