MS05-P14 Galectin-3: Studying role of  fluorines  in the protein-ligand  interaction  to achieve high affinity and selectivity rohit kumar (Biochemistry and Structural Biology, Lund university, Lund, Sweden) Kristoffer Peterson (CAS, Lund University, Lund, Sweden) Ulf Nilsson (CAS, Lund University, Lund, Sweden) Derek Logan (Biochemistry and Structural Biology, Lund university, lund, Sweden)email: belongs to the galectin family that recognizes carbohydrates. It has a highly conserved carbohydrate recognition domain (CRD) of 130 residues, which is responsible for binding to beta-galactosides. Galectin-3 has been shown to be involved in cancer, angiogenesis and stroke. Its involvement in these important diseases makes it a wonderful drug target. Our previous work1 showed the mode of binding of lactose and role of structured water molecules in carbohydrate binding site. These results prompted us to explore the molecular recognition and role of water molecules in designing high affinity inhibitors. Natural ligands of galectin-3 almost always have a galactose residue.
Selective small molecule galectin-3 inhibitors are valuable both as research tools to study protein-ligand interactions and as lead compounds in drug discovery. These compounds usually involve galactose-based derivatives, 1- and 3-substitutions of galactose. We have solved numerous protein-ligand crystal structures to study the effect of various substitutions. Fluorines are known to have diverse effects on physicochemical and conformational properties of ligands. Introduction of Fluorines at key positions in ligands has been proven to be promising strategy in lead optimization. Position and amount of fluorination has strong effect on the protein ligand interactions. Fluorines enhance ligand affinity by interacting with both the polar electropositive and hydrophobic groups in protein. Orthogonal multipolar C-F…C=O interactions with both peptide backbone and side chain carbonyls have been found important for Fluorines2.
Distinct fluorophilic environments in proteins are the ubiquitous peptide bonds, which undergo multipolar C-F ··· H-N, C-F ···C=O, and C-F ··· H-CR interactions. Here we report several structures of galectin-3 CRD with mono-galactose based compounds having fluorines in different positions and numbers.

1. Saraboji K, HÃ¥kansson M, Genheden S, Diehl C, Qvist J, Weininger U, Nilsson UJ, Leffler H, Ryde U, Akke M, Logan DT. The carbohydrate-binding site in galectin-3 is preorganized to recognize a sugarlike framework of oxygens: ultra-high-resolution structures and water dynamics. Biochemistry. 2012 Jan 10;51(1):296-306. doi: 10.1021/bi201459p. Epub 2011 Dec 7. PubMed PMID: 22111949

2. Zhou P, Zou J, Tian F, Shang Z. Fluorine bonding--how does it work in protein-ligand interactions? J Chem Inf Model. 2009 Oct;49(10):2344-55. doi:10.1021/ci9002393. PubMed PMID: 19788294

Keywords: Galectin-3, Protein-ligand interactions, fluorines