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

<p>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 <i>in silico</i> methods. Promising candidates were identified after virtual screening, which may restrict TLR4−MD-2 protein–protein interaction. <i>In silico</i> off-target profiling over the virtually screened compounds revealed other possible molecular targets. Two of the virtually screened compounds (C11 and C15) were predicted to have an inhibitory concentration in μM range after HYDE assessment. Molecular dynamics simulation study performed for these two compounds in complex with target protein confirms the stability of the complex. After virtual high throughput screening we found selective hTLR4−MD-2 inhibitors, which may have therapeutic potential to target chronic inflammatory diseases.