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Determining the most relevant crystal structure to virtually identify type 1 inhibitors of c-Met: Part A

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Title Determining the most relevant crystal structure to virtually identify type 1 inhibitors of c-Met: Part A
 
Creator Begwani, Khushboo
Joshi, Urmila
 
Subject Type 1 inhibitors of c-Met
Self-docking
Cross-docking
Enrichment parameters
 
Description 613-620
c-Met is a receptor tyrosine kinase, which plays a crucial role in cell proliferation, migration and angiogenesis. Its
dysregulation results in aberrant signalling, resulting in tumor growth and metastasis; an important target in cancer treatment.
Multiple crystal structures are available from the protein data bank of c-Met bound to various inhibitors. Since the receptor
tyrosine kinases are conformationally flexible receptors, each of these crystal structures represents a distinct conformation
suited to accommodate the ligand. For the identification of new ligands as inhibitors of c-Met using computational methods,
such a situation presents a challenge, as the use of some crystal structures for docking may result in the identification of false
negatives. To address this issue, we have screened the available crystal structures of c-Met; bound to Type 1 inhibitors
systematically to identify the most relevant crystal structure which can be used for docking. The procedure involved
ascertaining the presence of Type 1 inhibitors in the crystal structure, self-docking to ensure the suitability of docking protocol,
cross-docking to establish the ability of that crystal structure to accommodate chemically distinct ligands and followed by
judging the ability of the top-ranked crystal structures to identify actives over decoys preferentially. The Enrichment Factors
and other statistical parameters such as the number of outranking decoys, Robust Initial Enhancement, ROC, BEDROC and
Diversity Enrichment Factor were also calculated and analysed. All the results pointed towards 3ZXZ outperforming in all the
tests and thus can be used as the most appropriate crystal structure for virtual screening of Type 1 inhibitors of c-Met.
 
Date 2024-06-21T11:35:42Z
2024-06-21T11:35:42Z
2024-06
 
Type Article
 
Identifier 2583-1321 (Online); 0019-5103 (Print)
http://nopr.niscpr.res.in/handle/123456789/64072
https://doi.org/10.56042/ijc.v63i6.9771
 
Language en
 
Publisher NIScPR-CSIR, India
 
Source IJC Vol.63(06) [June 2024]