Boronic Acid Group: A Cumbersome False Negative Case in the Process of Drug Design.
Herein we present, an exhaustive docking analysis considering the case of autotaxin (ATX). HA155, a small molecule inhibitor of ATX, is co-crystallized. In order to further extract conclusions on the nature of the bond formed between the ligands and the amino acid residues of the active site, density functional theory (DFT) calculations were undertaken. However, docking does not provide reproducible results when screening boronic acid derivatives and their binding orientations to protein drug targets. Based on natural bond orbital (NBO) calculations, the formed bond between Ser/Thr residues is characterized more accurately as a polar covalent bond instead of a simple nonpolar covalent one. The presented results are acceptable and could be used in screening as an active negative filter for boron compounds. The hydroxyl groups of amino acids are bonded with the inhibitor's boron atom, converting its hybridization to sp³.
Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, University Campus, 54124 Thessaloniki, Greece. sotikats@pharm.auth.gr.
Sotirios
S
Katsamakas
Laboratory of Applied Quantum Chemistry, School of Chemistry, Aristotle University of Thessaloniki, University Campus, 54124 Thessaloniki, Greece. anastp@chem.auth.gr.
Anastasios G
AG
Papadopoulos
Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, University Campus, 54124 Thessaloniki, Greece. hadjipav@pharm.auth.gr.
Dimitra
D
Hadjipavlou-Litina
D001897:Boronic Acids / Q000737:chemistry*; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry*; D000099189:Lysophospholipase D
D001897:Boronic Acids; D004791:Enzyme Inhibitors; D010727:Phosphoric Diester Hydrolases; D000099189:Lysophospholipase D
autotaxin; boronic acid; drug design; organoboron; virtual screening; warhead