title: Ligand binding cooperativity: Bioisosteric replacement of CO with SO2 among thrombin inhibitors.
abstract: Ligand-protein binding is a complex process that involves the formation of number of non-covalent interactions, e.g. H-bonds and hydrophobic interactions, between the ligand and the protein host. Upon binding, ligand functional groups can act synergistically (positive cooperativity) to improve the overall ligand binding affinity beyond what would be expected from their individual contributions. In this study, using thrombin as a protein model system, we evaluated the effect of the bioisosteric replacement of a carbonyl functionality with a sulphonyl functionality on positive cooperativity between their H-bonds with thrombin and hydrophobic binding in the adjacent S3 pocket. The positive cooperativity observed was greatly reduced when replacing the carbonyl group with a sulphonyl group. Evaluating how bioisosteric replacements affect cooperativity is important for making better informed ligand optimization SAR decisions.
authors.affiliation: Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY 14260, United States; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Helwan University, Helwan, Egypt. Electronic address: ahmedmoh@buffalo.edu.
authors.forename: Ahmed M
authors.initials: AM
authors.lastname: Said
authors.affiliation: Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY 14260, United States. Electronic address: hangauer@buffalo.edu.
authors.forename: David G
authors.initials: DG
authors.lastname: Hangauer
mesh_terms: D000991:Antithrombins / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D020134:Catalytic Domain; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D062105:Molecular Docking Simulation; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013458:Sulfur Dioxide / Q000737:chemistry; D013816:Thermodynamics; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000991:Antithrombins; D008024:Ligands; D013458:Sulfur Dioxide; D013917:Thrombin
keywords: Bioisosteric replacement; Cooperativity; Hydrogen bonding; Hydrophobic binding; Ligand–protein binding; Nonadditivity; Thrombin