Abstract

Quorum sensing is being investigated as an alternative therapeutic strategy in antibacterial drug discovery to combat bacterial resistance. LsrK is an autoinducer-2 kinase, playing a key role in the phosphorylation of autoinducer-2 (AI-2) signalling molecules involved in quorum sensing. Inhibiting LsrK could result in reduced pathogenicity by interfering with the quorum sensing signalling. Previously, we have generated homology models to identify LsrK inhibitors using structure-based virtual screening and successfully found the first class of LsrK inhibitors. While conducting these studies, the crystal structure of LsrK was released providing us an opportunity to inspect the reliability and quality of our models. Structural analysis of crystal structure and homology models revealed the consistencies of constructed models with crystal structure in the structural fold and binding site. Further, binding characteristics and conformational changes are investigated using molecular dynamics. These simulations provided us insights into the protein function and flexibility that need to be considered during the structure-based drug design studies targeting LsrK.