Affinity and selectivity of protein–ligand recognition: a minor chemical modification changes carbonic anhydrase binding profile

Audrius Zakšauskas; Vaida Paketurytė-Latvė; Alberta Jankūnaitė; Edita Čapkauskaitė; Yann Becart; Alexey Smirnov; Klára Pospíšilová; Janis Leitans; Jiří Brynda; Andris Kazaks; Lina Baranauskienė; Elena Manakova; Saulius Gražulis; Visvaldas Kairys; Kaspars Tars; Pavlína Řezáčová; Daumantas Matulis

doi:10.1021/acs.jmedchem.5c01421

Title	Affinity and selectivity of protein–ligand recognition: a minor chemical modification changes carbonic anhydrase binding profile
Authors	Zakšauskas, Audrius ; Paketurytė-Latvė, Vaida ; Jankūnaitė, Alberta ; Čapkauskaitė, Edita ; Becart, Yann ; Smirnov, Alexey ; Pospíšilová, Klára ; Leitans, Janis ; Brynda, Jiří ; Kazaks, Andris ; Baranauskienė, Lina ; Manakova, Elena ; Gražulis, Saulius ; Kairys, Visvaldas ; Tars, Kaspars ; Řezáčová, Pavlína ; Matulis, Daumantas
DOI	10.1021/acs.jmedchem.5c01421
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Is Part of	Journal of medicinal chemistry.. Washington : American Chemical Society. 2025, vol. 68, iss. 16, p. 17752-17773.. ISSN 0022-2623. eISSN 1520-4804
Keywords [eng]	conformation ; ligands ; molecules ; peptides and proteins ; sulfones
Abstract [eng]	Discovery of small-molecule drugs relies on their strong binding affinity compared to nontarget proteins, thus possessing selectivity. Minor chemical structure changes usually exhibit little change in the compound efficacy, with rare exceptions. We developed a series of nearly 50 ortho-substituted benzenesulfonamides and experimentally measured their interactions with the 12 catalytically active human carbonic anhydrase (CA) isozymes. Inhibitors were designed using seven different substituent groups, including 4-sulfanyl-substituted 3-sulfamoyl benzoates and benzamides, 4-sulfinyl-substituted 3-sulfamoyl benzoates and benzamides, 4-sulfonyl-substituted 3-sulfamoyl benzoates and benzamides, and 4-amino-substituted benzamides. The oxidation state of sulfur at the ortho position significantly influenced the compound’s affinity for CAIX, a target for anticancer drugs, demonstrating affinities hundreds of thousands of times stronger than related compounds. Coupled with X-ray crystal structures and molecular docking, the relationship between structure and thermodynamics offers insights into how small changes in the structure lead to significant changes in affinity for drug design.
Published	Washington : American Chemical Society
Type	Journal article
Language	English
Publication date	2025
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„Affinity and selectivity of protein–ligand recognition: a minor chemical modification changes carbonic anhydrase binding profile“