Ligand-based pharmacophore modeling and molecular dynamic simulation approaches to identify putative MMP-9 inhibitors

MMP-9 is a calcium-dependent zinc endopeptidase that plays a crucial role in various diseases and is a ubiquitous target for many classes of drugs. The availability of MMP-9 crystal structure in combination with aryl sulfonamide anthranilate hydroxamate inhibitor facilitates to accentuate the comput...

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Bibliographic Details
Published in:RSC advances 2021-08, Vol.11 (43), p.2682-26831
Main Authors: Sanapalli, Bharat Kumar Reddy, Yele, Vidyasrilekha, Jupudi, Srikanth, Karri, Veera Venkata Satyanarayana Reddy
Format: Article
Language:English
Subjects:
Affinity
Binding
Chemistry
Crystal structure
Free energy
Hypotheses
Inhibitors
Ligands
Matrix metalloproteinases
Modelling
Molecular dynamics
Pharmacology
Reliability analysis
Screening
Sulfonamides
Three dimensional models
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Summary:MMP-9 is a calcium-dependent zinc endopeptidase that plays a crucial role in various diseases and is a ubiquitous target for many classes of drugs. The availability of MMP-9 crystal structure in combination with aryl sulfonamide anthranilate hydroxamate inhibitor facilitates to accentuate the computer-aided screening of MMP-9 inhibitors with the presumed binding mode. In the current study, ligand-based pharmacophore modeling and 3D-QSAR analysis were performed using 67 reported MMP-9 inhibitors possessing p IC 50 in the range of 5.221 to 9.000. The established five-point hypothesis model DDHRR_1 was statistically validated using various parameters R 2 (0.9076), Q 2 (0.8170), and F value (83.5) at a partial least square of four. Hypothesis validation and enrichment analysis were performed for the generated hypothesis. Further, Y-scrambling and Xternal validation using mean-absolute error-based criteria were performed to evaluate the reliability of the model. Docking in the XP mode and binding free energy was calculated for 67 selected ligands to explore the key binding interactions and binding affinity against the MMP-9 enzyme. Additionally, high-throughput virtual screening was carried out for 2.3 million chemical molecules to explore the potential virtual hits, and their predicted activity was calculated. Thus, the results obtained aid in developing novel MMP-9 inhibitors with significant activity and binding affinity. MMP-9 is a calcium-dependent zinc endopeptidase that plays a crucial role in various diseases and is a ubiquitous target for many classes of drugs.
ISSN:2046-2069
2046-2069
DOI:10.1039/d1ra03891e