Correlations Between Inhibitor Binding Thermodynamics and Co-crystal Structures with Carbonic Anhydrases

  • Alexey Smirnov
  • Elena Manakova
  • Daumantas MatulisEmail author


In order to be able to design chemical compounds that recognize a particular CA isoform, meaning that they would bind particular isoform with high affinity while not binding other isoforms, it is important to understand how compounds recognize the protein surface. To understand which structural features yield what types of changes in the binding energetics, we search for correlations between compound–isoform co-crystal structures and intrinsic thermodynamics of binding. The compounds are being compared by arranging them in matched molecular pairs that differ by a single functional group responsible for the change in binding thermodynamics. Part of the ligands bound in similar orientations of the benzenesulfonamide ring, while others bound in dissimilar orientation. All similar binders exhibited significant increase in entropic forces upon increase in the buried surface of the compounds, while dissimilar binders had various thermodynamics. Several mechanisms were identified, perfect geometry fit and a molecular trap. The softness of the CA active site and the water molecules are also discussed.


  1. 1.
    Klebe, G.: Applying thermodynamic profiling in lead finding and optimization. Nat. Rev. Drug Discov. 14, 95–110 (2015)CrossRefGoogle Scholar
  2. 2.
    Geschwindner, S., Ulander, J., Johansson, P.: Ligand binding thermodynamics in drug discovery: still a hot tip? J. Med. Chem. 58, 6321–6335 (2015)CrossRefGoogle Scholar
  3. 3.
    Claveria-Gimeno, R., Vega, S., Abian, O., Velazquez-Campoy, A.: A look at ligand binding thermodynamics in drug discovery. Expert Opin. Drug Discov. 12, 363–377 (2017)CrossRefGoogle Scholar
  4. 4.
    Freire, E.: Do enthalpy and entropy distinguish first in class from best in class? Drug Discov. Today 13, 869–874 (2008)CrossRefGoogle Scholar
  5. 5.
    Snyder, P.W., Lockett, M.R., Moustakas, D.T., Whitesides, G.M.: Is it the shape of the cavity, or the shape of the water in the cavity? Eur. Phys. J. Spec. Top. 223, 853–891 (2013)CrossRefGoogle Scholar
  6. 6.
    Smirnov, A., Zubrienė, A., Manakova, E., Gražulis, S., Matulis, D.: Crystal structure correlations with the intrinsic thermodynamics of human carbonic anhydrase inhibitor binding. PeerJ 6, e4412 (2018)CrossRefGoogle Scholar
  7. 7.
    Zubrienė, A., et al.: Intrinsic thermodynamics of 4-substituted-2,3,5,6-tetrafluorobenzenesulfonamide binding to carbonic anhydrases by isothermal titration calorimetry. Bio-phys. Chem. 205, 51–65 (2015)Google Scholar
  8. 8.
    Fisher, Z., et al.: Neutron structure of human carbonic anhydrase II: a hydrogen-bonded water network “switch” is observed between pH 7.8 and 10.0. Biochemistry 50, 9421–9423 (2011). PDB ID: 3TMJCrossRefGoogle Scholar
  9. 9.
    Michalczyk, R., et al.: Joint neutron crystallographic and nmr solution studies of tyr residue ionization and hydrogen bonding: implications for enzyme-mediated proton transfer. Proc. Natl. Acad. Sci. U. S. A. 112, 5673–5678 (2015). PDB ID: 4Q49, 4Y0JCrossRefGoogle Scholar
  10. 10.
    Kovalevsky, A., et al.: “To be or not to be” protonated: atomic details of human carbonic anhydrase-clinical drug complexes by neutron crystallography and simulation. Structure 26, 383–390 (2018)CrossRefGoogle Scholar
  11. 11.
    Aggarwal, M., et al.: Neutron structure of human carbonic anhydrase II in complex with methazolamide: mapping the solvent and hydrogen-bonding patterns of an effective clinical drug. IUCrJ 3, 319–325 (2016)CrossRefGoogle Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Alexey Smirnov
    • 1
  • Elena Manakova
    • 2
  • Daumantas Matulis
    • 1
    Email author
  1. 1.Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences CenterVilnius UniversityVilniusLithuania
  2. 2.Department of Protein-DNA Interactions, Institute of Biotechnology, Life Sciences CenterVilnius UniversityVilniusLithuania

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