Crystal structure correlations with the intrinsic thermodynamics of human carbonic anhydrase inhibitor binding

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.

Methyl 2-Halo-4-Substituted-5-Sulfamoyl-Benzoates as High Affinity and Selective Inhibitors of Carbonic Anhydrase IX

“…The pairs of compounds bound to the same CA isozyme analyzed in Figure 2 D and Figure 3 C,D had the following common features: the positions and the binding affinities of the compounds in the pairs were the same or similar. Analogous observations were made previously [ 21 ], and such pairs were called “similar” binders. In pairs of “similar” binders, the additional hydrophobic surface did not produce additional interactions with the active site of CA.…”

Isothermal Analysis of ThermoFluor Data can readily provide Quantitative Binding Affinities

“…We next applied this approach to study a different protein, with multiple ligands spanning a broad range of binding affinities. We selected another model system that has been frequently used in calorimetric studies 23,24,38,45,62 , carbonic anhydrase (isoforms I and II). From among commercially-available inhibitors of these two enzymes we selected the weak inhibitor sulfanilamide (SULFA, mM K i ) and the potent inhibitor trifluoromethanesulfonamide (TFMSA, nM K i ).…”

Thermodynamic, kinetic, and structural parameterization of human carbonic anhydrase interactions toward enhanced inhibitor design

“…29.Comparison of the binding thermodynamic parameters in structurally-related compound pairs arranged according to the buried and accessible surface areas (BSA + ASA) which were calculated from the crystal structures as described by Smirnov et al . (2018). Panels ( a ) and ( b ) show the Gibbs energies of binding, ( c ) and ( d ) the intrinsic enthalpies of binding, and ( e ) and ( f ) – the entropies multiplied by the absolute temperature.…”