Severity: Warning
Message: file_get_contents(https://...@gmail.com&api_key=61f08fa0b96a73de8c900d749fcb997acc09): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
Filename: helpers/my_audit_helper.php
Line Number: 143
Backtrace:
File: /var/www/html/application/helpers/my_audit_helper.php
Line: 143
Function: file_get_contents
File: /var/www/html/application/helpers/my_audit_helper.php
Line: 209
Function: simplexml_load_file_from_url
File: /var/www/html/application/helpers/my_audit_helper.php
Line: 3098
Function: getPubMedXML
File: /var/www/html/application/controllers/Detail.php
Line: 574
Function: pubMedSearch_Global
File: /var/www/html/application/controllers/Detail.php
Line: 488
Function: pubMedGetRelatedKeyword
File: /var/www/html/index.php
Line: 316
Function: require_once
Severity: Warning
Message: Attempt to read property "Count" on bool
Filename: helpers/my_audit_helper.php
Line Number: 3100
Backtrace:
File: /var/www/html/application/helpers/my_audit_helper.php
Line: 3100
Function: _error_handler
File: /var/www/html/application/controllers/Detail.php
Line: 574
Function: pubMedSearch_Global
File: /var/www/html/application/controllers/Detail.php
Line: 488
Function: pubMedGetRelatedKeyword
File: /var/www/html/index.php
Line: 316
Function: require_once
MMP-9 is an attractive target for the development of new anticancer drugs. In the current study, pharmacophore modeling was employed using two highly active and selective gelatinase inhibitors obtained from two X-ray crystal structures (PDB IDs: and ) to identify novel selective MMP-9 inhibitors. The derived model was refined manually and also validated by the GH scoring method. The refined pharmacophore model, ADRR, was able to retrieve 86% of actives with a GH score of 0.774, indicating that the model was capable of retrieving the active MMP-9 inhibitors. ADRR was used to screen 2 838 166 unique structures. Hit filtration was carried out using a fitness score >1.5 and drug-likeness properties. Hierarchical clustering generates 33 clusters based on diversity. A total of 33 molecules were obtained and these molecules were taken for cross-docking studies with 5 subtype MMPs. Among 33 tested, 2 molecules, P10A-0000088030 (Lig-1) and P10A-0001383812 (Lig-2), were found to have the highest docking scores (-8.59 kcal mol(-1) and -8.27 kcal mol(-1)) towards MMP-9 compared with the other MMPs. Further MM-GBSA analysis was performed for two hits with 5 subtype MMPs to reveal the essential features that contribute to selectivity. The results showed that van der Waals contributions play a central role in determining the selectivity of MMP-9 inhibitors. Molecular dynamics studies were carried out for total time of 330 ns to assess the stability of ligands at the active site. MD analysis showed that binding of Lig-1 with MMP-9 is stable compared to that with Lig-2. Hence, we suggest the Lig-1 compound as a good lead in designing novel potent inhibitors of MMP-9.
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Source |
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http://dx.doi.org/10.1039/c6mb00066e | DOI Listing |
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