STRUCTURE-BASED DESIGN OF GLYCOMIMETIC LIGANDS FOR THE N-TERMINAL DOMAIN OF BC2L-C LECTIN

The prevalence of drug-resistant infections has challenged the existing treatment regimen using antibiotics. There is a need to discover and employ alternative and complementary therapies to counteract these life threatening infections. In fast few decades, the use of anti-adhesion molecules targeting virulence factors such as lectins has been proven an attractive approach to counteract the infections by disarming the pathogens. This thesis work aimed to design glycomimetic antagonists of the N-terminal domain of the BC2L-C lectin (BC2L-C-nt) from the drug-resistant pathogen known as B. cenocepacia. We employed a fragment-based approach to design glycomimetic antagonists of the target protein (BC2L-C-nt). The initial studies were focused towards the binding site prediction and target evaluation by computational tools which identified additional druggable regions near the fucoside binding site in BC2L-C-nt. These additional regions have been explored further to evaluate the druggability by employing virtual screening of a small fragment library. This identified an interesting region (region ‘X’) that could host the drug-like fragments by establishing some key interactions. These interactions with the lectin have been confirmed using a group of biophysical techniques, including X-ray crystallography. Remarkably, the binding mode of one of the fragment (KL3) has been validated by X-ray crystallography at high resolution confirming the ability of site X to host drug-like fragments. Further, the fragments have been chemically connected to the fucose core to obtain high-affinity bifunctional glycomimetic ligands. Interestingly, the crystal complexes of BC2L-C-nt with two bifunctional glycomimetic ligands again confirmed the druggability of the identified site, thus also validated the computational predictions. Hence, the first generation of glycomimetic ligands with binding affinities in micromolar range have been successfully designed. These glycomimetics provide further opportunities to design high-affinity ligands. Future studies based on structure-based approaches and robust synthetic routes to synthesize glycomimetics can lead towards the high-affinity ligands as anti-adhesive agents against B. cenocepacia.