Abstract
The structure-thermodynamics correlation analysis was performed for a series of fluorine- and chlorine-substituted benzenesulfonamide inhibitors binding to several human carbonic anhydrase (CA) isoforms. The total of 24 crystal structures of 16 inhibitors bound to isoforms CA I, CA II, CA XII, and CA XIII provided the structural information of selective recognition between a compound and CA isoform. The binding thermodynamics of all structures was determined by the analysis of binding-linked protonation events, yielding the intrinsic parameters, i.e., the enthalpy, entropy, and Gibbs energy of binding. Inhibitor binding was compared within structurally similar pairs that differ by para- or meta-substituents enabling to obtain the contributing energies of ligand fragments. The pairs were divided into two groups. First, similar binders—the pairs that keep the same orientation of the benzene ring exhibited classical hydrophobic effect, a less exothermic enthalpy and a more favorable entropy upon addition of the hydrophobic fragments. Second, dissimilar binders—the pairs of binders that demonstrated altered positions of the benzene rings exhibited the non-classical hydrophobic effect, a more favorable enthalpy and variable entropy contribution. A deeper understanding of the energies contributing to the protein-ligand recognition should lead toward the eventual goal of rational drug design where chemical structures of ligands could be designed based on the target protein structure.
Highlights
Low molecular weight compound recognition by a target protein is still rather poorly understood hindering efficient rational design of novel molecules that would tightly and bind selectively to the target protein and could be developed into an efficient and non-toxic drug that does not bind and influence the function of other vital proteins
A series of 24 crystal structures of complexes between four carbonic anhydrase (CA) isoforms and 16 aromatic benzenesulfonamides were solved by X-ray crystallography characterizing the structural aspect of the interaction
To characterize the same interactions energetically, the observed affinities of binding for each protein-ligand pair were determined by the fluorescent thermal shift assay (FTSA), and the observed enthalpies were determined by isothermal titration calorimetry (ITC)
Summary
Low molecular weight compound recognition by a target protein is still rather poorly understood hindering efficient rational design of novel molecules that would tightly and bind selectively to the target protein and could be developed into an efficient and non-toxic drug that does not bind and influence the function of other vital proteins. Protein-compound complexes could be characterized structurally and thermodynamically. Correlations between these approaches is the main focus of this manuscript. How to cite this article Smirnov et al (2018), Crystal structure correlations with the intrinsic thermodynamics of human carbonic anhydrase inhibitor binding. Carbonic anhydrases (CAs, EC 4.2.1.1) are ubiquitous metallo-enzymes which catalyze the hydration reaction of carbon dioxide into bicarbonate. Human CAs belong to the αfamily comprised of fifteen isozymes which have different cellular localization, distribution, kinetic properties, expression levels, and oligomerization state (Sly & Hu, 1995; Supuran, 2008; Supuran, 2015; Alterio et al, 2012). CAs are involved in many physiological and pathological processes. Twelve of the isozymes (isoforms) contain Zn(II) metal in the active site coordinated by three histidines, while remaining three CA isozymes do not possess any catalytic activity because they do not have Zn(II) in the active site due to the absence of one or more His residues (Aspatwar et al, 2014) needed for the coordination of the metal
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