DISSECTING MOLECULAR INTERACTIONS BETWEEN CXCL8 AND NAPHTHALENE DERIVATIVES USING COMPUTATIONAL AND BIOPHYSICAL APPROACHES

Abstract

Chemokines are low molecular weight (8-14 kiloDalton) signalling proteins belonging to a sub-family of cytokines. Chemokines are secreted by immune cells at the time of inflammation and injury. They act as chemotactic proteins that regulate the migration, positioning and proliferation of various classes of leukocytes [1]. Chemokines are classified into four different sub-classes on the basis of positioning of two cysteine residues in the protein. These sub classes, namely, C, CC, CXC and CXC3C have been discussed in further detail below. Chemokines bind to specific G-protein coupled receptors with varying binding specificity between different chemokines and receptors. CXCL8 is a member of CXC chemokine sub family that plays a central role in neutrophil trafficking to the site of inflammation. CXCL8, also known as Neutrophil Activating Chemokine (NAC), regulates neutrophil transmigration by activating CXCR1 and CXCR2 receptors for further downstream signalling. CXCL8 is secreted manly by monocytes in response to inflammatory stimulus. Interactions of CXCL8 with cell surface and extracellular matrix (ECM) GAGs is responsible for the mediation of chemokine oligomeration and interaction with cell surface receptors. GAGs are highly negatively charged oligosaccharides and interact with proteions mainly by electrostatic interactions with positively charged residues of protein. Negatively charged small molecules such as naphthalene derivatives with negatively charged sulphate groups can be used as inhibitors for GAG-CXCL8 interactions. The binding of these small molevule inhibitors to positively charged residues of protein may prevent GAG-CXCL8 binding by masking the binding pocket occupied by GAGs. The following study was designed with the following objectives: