Insights into Modeling Approaches in Chemistry: Assessing Ligand‐Protein Binding Thermodynamics Based on Rigid‐Flexible Model Molecules

Abstract

In the field of chemistry, model compounds find extensive use for investigating complex objects. One prime example of such object is the protein‐ligand supramolecular interaction. Prediction the enthalpic and entropic contribution to the free energy associated with this process, as well as the structural and dynamic characteristics of protein‐ligand complexes poses considerable challenges. This review exemplifies modeling approaches used to study protein‐ligand binding (PLB) thermodynamics by employing pairs of conformationally constrained/flexible model molecules. Strategically designing the model molecules can reduce the number of variables that influence thermodynamic parameters. This enables scientists to gain deeper insights into the enthalpy and entropy of PLB, which is relevant for medicinal chemistry and drug design. The model studies reviewed here demonstrate that rigidifying ligands may induce compensating changes in the enthalpy and entropy of binding. Some “rules of thumb” have started to emerge on how to minimize entropy‐enthalpy compensation and design efficient rigidified or flexible ligands.

Bicyclo[m.n.k]alkane Building Blocks as Promising Benzene and Cycloalkane Isosteres: Multigram Synthesis, Physicochemical and Structural Characterization

“…Column chromatography was performed using Kieselgel Merck 60 (230-400 mesh) as the stationary phase. 1 H, 13 C and 19 F NMR spectra were recorded on an Agilent ProPulse 600 spectrometer (at 600 MHz for 1 H NMR, 151 MHz for 13 C NMR), Bruker 170 Avance 500 spectrometer (at 500 MHz for 1 H NMR, 126 MHz for 13 C NMR and 470 MHz for 19 F NMR) or Varian Unity Plus 400 spectrometer (at 400 MHz for 1 H NMR, 101 MHz for 13 C NMR and 376 MHz for 19 F NMR). NMR chemical shifts are reported in ppm (δ scale) downfield from TMS as an internal standard and are referenced using residual NMR solvent peaks at 7.26 and 77.16 ppm for 1 H and 13 C in CDCl 3 , 2.50 and 39.52 ppm for 1 H and 13 C in DMSO-d 6 .…”

“…Nature itself widely utilizes carbocyclic molecules with mono‐ and bicyclic framework that have a wide range of biological activities [5–11] . The rigidity of bicyclic scaffolds has noticeable features in drug discovery since it may decrease the enthalpic penalty of the protein‐ligand binding and improve overall physicochemical properties of the molecule [5–7,12–14] . In the last few years, bicyclo[m.n.k]alkanes have attracted much attention in medicinal chemistry as non‐classical isosteres of benzene and cycloalkanes that allow improve pharmacokinetic parameters of the compound and fine‐tune its affinity to the biological target [15–21] .…”

“…[5][6][7][8][9][10][11] The rigidity of bicyclic scaffolds has noticeable features in drug discovery since it may decrease the enthalpic penalty of the protein-ligand binding and improve overall physicochemical properties of the molecule. [5][6][7][12][13][14] In the last few years, bicyclo[m.n.k]alkanes have attracted much attention in medicinal chemistry as non-classical isosteres of benzene and cycloalkanes that allow improve pharmacokinetic parameters of the compound and fine-tune its affinity to the biological target. [15][16][17][18][19][20][21] In this view, bicyclo[1.1.1]pentanes (BCPs), [22,23] -[2.1.1]hexanes, [24] -[2.2.1]heptanes (norbornanes), -[3.1.1]heptanes, [25] -[2.2.2]octanes, [26] or -[2.2.0]hexanes ([2]ladderanes) [27] can be particularly outlined (Scheme 1, A).…”

Chemistry in Ukraine

“…Komarov, Grygorenko, and co-workers present a critical review [19] that exemplifies modelling approaches used to study protein-ligand binding thermodynamics by employing pairs of conformationally constrained/flexible model molecules. The authors discuss the trends in model studies, how to minimize entropy-enthalpy compensation and efficiently design rigidified of flexible ligands.…”