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: 994
Function: getPubMedXML
File: /var/www/html/application/helpers/my_audit_helper.php
Line: 3134
Function: GetPubMedArticleOutput_2016
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
Protein-protein interactions (PPIs) are essential for biological processes including immune reactions and diseases. Inhibition of PPIs by drug-like compounds is a common basis for therapeutic approaches. In many cases the flat interface of PP complexes prevents discovery of specific compound binding to cavities on one partner and PPI inhibition. However, frequently new pockets are formed at the PP interface that allow accommodation of stabilizers which is often as desirable as inhibition but a much less explored alternative strategy. Herein, we employ molecular dynamics simulations and pocket detection to investigate 18 known stabilizers and associated PP complexes. For most cases, we find that a dual-binding mechanism, a similar stabilizer interaction strength with each protein partner, is an important prerequisite for effective stabilization. A few stabilizers follow an allosteric mechanism by stabilizing the protein bound structure and/or increase the PPI indirectly. On 226 protein-protein complexes, we find in >75% of the cases interface cavities suitable for binding of drug-like compounds. We propose a computational compound identification workflow that exploits new PP interface cavities and optimizes the dual-binding mechanism and apply it to 5 PP complexes. Our study demonstrates a great potential for PPI stabilizers discovery with a wide range of therapeutic applications.
Download full-text PDF |
Source |
---|---|
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10214505 | PMC |
http://dx.doi.org/10.1021/acscentsci.3c00003 | DOI Listing |
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!