Structural insights into pharmacophore-assisted in silico identification of protein-protein interaction inhibitors for inhibition of human toll-like receptor 4 - myeloid differentiation factor-2 (hTLR4-MD-2) complex

Journal of Biomolecular Structure & Dynamics
Vinita Mishra, Chandramani Pathak

Abstract

Toll-like receptor 4 (TLR4) is a member of Toll-Like Receptors (TLRs) family that serves as a receptor for bacterial lipopolysaccharide (LPS). TLR4 alone cannot recognize LPS without aid of co-receptor myeloid differentiation factor-2 (MD-2). Binding of LPS with TLR4 forms a LPS-TLR4-MD-2 complex and directs downstream signaling for activation of immune response, inflammation and NF-κB activation. Activation of TLR4 signaling is associated with various pathophysiological consequences. Therefore, targeting protein-protein interaction (PPI) in TLR4-MD-2 complex formation could be an attractive therapeutic approach for targeting inflammatory disorders. The aim of present study was directed to identify small molecule PPI inhibitors (SMPPIIs) using pharmacophore mapping-based approach of computational drug discovery. Here, we had retrieved the information about the hot spot residues and their pharmacophoric features at both primary (TLR4-MD-2) and dimerization (MD-2-TLR4*) protein-protein interaction interfaces in TLR4-MD-2 homo-dimer complex using in silico methods. Promising candidates were identified after virtual screening, which may restrict TLR4-MD-2 protein-protein interaction. In silico off-target profiling over the virtuall...Continue Reading

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Citations

Feb 7, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Qurat Ul AinSangdun Choi
Sep 25, 2021·Journal of Chemical Information and Modeling·Cristina González-FernándezInmaculada Ortiz

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Methods Mentioned

BETA
ubiquitination
MDS

Software Mentioned

poseview plus
Star Optibrium
FTMap
InteractiVenn
MDS
admetSAR
HotRegion
StarDrop Optibrium
Force Field Toolkit Ions
cytoscape

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