Protein–Ligand Interactions: Thermodynamic Effects Associated with Increasing the Length of an Alkyl Chain

Abstract

Thermodynamic parameters were determined for complex formation between the Grb2 SH2 domain and tripeptides of the general form Ac-pTyr-Xaa-Asn in which the Xaa residue bears a linear alkyl chain varying in length from 1–5 carbon atoms. Binding affinity increases upon adding a methylene group to the Ala derivative, but further chain extension gives no extra enhancement in potency. The thermodynamic signatures of the ethyl and n-propyl derivatives are virtually identical as are those for the n-butyl and n-pentyl analogs. Crystallographic analysis of the complexes reveals a high degree of similarity in the structure of the domain and the bound ligands with the notable exception that there is a gauche interaction in the side chains in the bound conformations of ligands having n-propyl, n-butyl, and n-pentyl groups. However, eliminating this unfavorable interaction by introducing a Z-double bond into the side chain of the n-propyl analog does not result in an increase in affinity. Increases in the amount of nonpolar surface that is buried upon ligand binding correlate with favorable changes in ΔH°, but these are usually offset by corresponding unfavorable changes in −TΔS°; there is little correlation of ΔCp with changes in the amount of buried nonpolar surface.

Discovery and Optimization of a Selective Ligand for the Switch/Sucrose Nonfermenting-Related Bromodomains of Polybromo Protein-1 by the Use of Virtual Screening and Hydration Analysis

“…Notably, systematic thermodynamic and structural studies of similar systems have shown that in many cases, increasing the length of an alkyl chain leads to gain in enthalpy that is, hence, fully offset by an unfavorable entropy change, thus affording a negative net effect on binding affinity. 66 In this study, we demonstrated the use of designing constructive interactions with the water environment of a protein/ligand system on the basis of utilizing available solvation mapping algorithms. In a theoretical druggability assessment of BRDs based on the available X-ray crystallographic data, the degree by which different members of the family constitute tractable drug targets was determined.…”

“…Nai ̈vely, it would seem that growing an alkyl chain into solvent where it cannot sustain considerable hydrophobic interactions with the protein, would not contribute favorably to ligand binding potency in any system. 66 However, in this study, it was shown that by considering the impact of solvent dynamics in binding, one can achieve optimization of a hit through alternative and possibly more efficient routes than those solely based on inspection of protein−ligand interactions. To facilitate this, one should go beyond utilization of structure-based techniques like protein X-ray crystallography or docking and also look to solvent mapping or other methods which take into consideration solvent dynamics.…”

Conformational Changes in Alkyl Chains Determine the Thermodynamic and Kinetic Binding Profiles of Carbonic Anhydrase Inhibitors

“…showed, expanding cyclic hydrocarbons as subunits at the center of a Grb2-SH2 domain inhibitor scaffold led to an increase in affinity based on the burial of hydrophobic surface area and, contrarily to the classical hydrophobic effect, with increasingly favorable enthalpic contributions . Furthermore, they demonstrated that this trend does not generally hold true, considering that, for aliphatic derivatives of this ligand series, a gain in Δ H ° was compensated by a decreasing contribution of − T Δ S ° . Krimmer et al .…”

“…10 Furthermore, they demonstrated that this trend does not generally hold true, considering that, for aliphatic derivatives of this ligand series, a gain in ΔH°was compensated by a decreasing contribution of −TΔS°. 11 Krimmer et al on the other hand showed that hydrophobic moieties of various lengths and degrees of branching can indeed be used to design water networks around solvent-exposed parts that contribute favorably to ΔG°. 12,13 Opposed to the medicinal chemistry dogma of attaching hydrophilic moieties to solvent-exposed parts of the ligand, Cramer et al demonstrated that it can be even detrimental to expose polar groups to the bulk solvent, rather than hydrophobic ones.…”

Natural Products and Their Mimics as Targets of Opportunity for Discovery

“…In other studies involving ligand binding to the Grb2-SH2 domain we investigated the effects of increasing the length of an alkyl chain at the pY+1 position, of introducing macrocyclic constraints in a peptide, as well as the effect of cation−π interactions . Collectively, these and other studies of protein–ligand interactions involving both the Grb2 and Src SH2 domains as well as numerous other biological systems reveal the difficulties of interpreting how even incremental structural changes in small molecules affect binding enthalpies and entropies in their interactions with a target protein .…”