Molecular recognition in biological systems relies on the existence of specific attractive interactions between two partner molecules. Structure-based drug design seeks to identify and optimize such interactions between ligands and their host molecules, typically proteins, given their three-dimensional structures. This optimization process requires knowledge about interaction geometries and approximate affinity contributions of attractive interactions that can be gleaned from crystal structure and associated affinity data.

Here we compile and review the literature on molecular interactions as it pertains to medicinal chemistry through a combination of careful statistical analysis of the large body of publicly available X-ray structure data and experimental and theoretical studies of specific model systems. We attempt to extract key messages of practical value and complement references with our own searches of the CSDa,(1) and PDB databases.(2) The focus is on direct contacts between ligand and protein functional groups, and we restrict ourselves to those interactions that are most frequent in medicinal chemistry applications. Examples from supramolecular chemistry and quantum mechanical or molecular mechanics calculations are cited where they illustrate a specific point. The application of automated design processes is not covered nor is design of physicochemical properties of molecules such as permeability or solubility.

Throughout this article, we wish to raise the readers’ awareness that formulating rules for molecular interactions is only possible within certain boundaries. The combination of 3D structure analysis with binding free energies does not yield a complete understanding of the energetic contributions of individual interactions. The reasons for this are widely known but not always fully appreciated. While it would be desirable to associate observed interactions with energy terms, we have to accept that molecular interactions behave in a highly nonadditive fashion.3,4 The same interaction may be worth different amounts of free energy in different contexts, and it is very hard to find an objective frame of reference for an interaction, since any change of a molecular structure will have multiple effects. One can easily fall victim to confirmation bias, focusing on what one has observed before and building causal relationships on too few observations. In reality, the multiplicity of interactions present in a single protein−ligand complex is a compromise of attractive and repulsive interactions that is almost impossible to deconvolute. By focusing on observed interactions, one neglects a large part of the thermodynamic cycle represented by a binding free energy: solvation processes, long-range interactions, conformational changes. Also, crystal structure coordinates give misleadingly static views of interactions. In reality a macromolecular complex is not characterized by a single structure but by an ensemble of structures. Changes in the degrees of freedom of both partners during the binding event have a large impact on binding free energy.

The text is organized in the following way. The first section treats general aspects of molecular design: enthalpic and entropic components of binding free energy, flexibility, solvation, and the treatment of individual water molecules, as well as repulsive interactions. The second half of the article is devoted to specific types of interactions, beginning with hydrogen bonds, moving on to weaker polar interactions, and ending with lipophilic interactions between aliphatic and aromatic systems. We show many examples of structure−activity relationships; these are meant as helpful illustrations but individually can never confirm a rule.

http://pubs.acs.org/doi/pdf/10.1021/jm100112j

A Medicinal Chemist’s Guide to Molecular Interactions

Hydrogen bonds provide most of the directional interactions that underpin protein folding, protein structure and molecular recognition. The core of most protein structures is composed of secondary structures such as α helix and β sheet. This satisfies the hydrogen-bonding potential between main chain carbonyl oxygen and amide nitrogen buried in the hydrophobic core of the protein. Hydrogen bonding between a protein and its ligands (protein, nucleic acid, substrate, effector or inhibitor) provides a directionality and specificity of interaction that is a fundamental aspect of molecular recognition. The energetics and kinetics of hydrogen bonding therefore need to be optimal to allow the rapid sampling and kinetics of folding, conferring stability to the protein structure and providing the specificity required for selective macromolecular interactions.



Key concepts: 



A hydrogen bond is formed by the interaction of a hydrogen atom that is covalently bonded to an electronegative atom (donor) with another electronegative atom (acceptor).




Hydrogen bonding confers rigidity to the protein structure and specificity to intermolecular interactions.




The accepted (and most frequently observed) geometry for a hydrogen bond is a distance of less than 2.5 A (1.9 A) between hydrogen and the acceptor and a donor-hydrogen-acceptor angle of between 90° and 180° (160°).




During protein folding, the burial of hydrophobic side-chains requires intramolecular hydrogen bonds to be formed between the main chain polar groups.




The most stable conformations of polypeptide chains that maximize intrachain hydrogen-bonding potential are α helices and β sheets.




Specificity in molecular recognition is driven by the interaction of complementary hydrogen-bonding groups on interacting surfaces.






Keywords:

hydrogen bond;
protein structure;
protein stability;
molecular recognition;
secondary structure

Hydrogen Bonds in Proteins: Role and Strength

COSMO-RS: An ionic liquid prescreening tool for gas hydrate mitigation

Fluorescence solvatochromism of lumichrome (LC) was studied by steady-state and time-resolved fluorescence spectroscopy. The excited-state properties of LC do not show any correlation with solvent polarity, however, reasonably good correlation with solvent ET(30) parameter was observed. A quantitative estimation of contribution from different solvatochromic parameters, like solvent polarizability (π*), hydrogen bond donor (α), and hydrogen bond acceptor (β) ability of the solvent, was made using linear free energy relationship on the basis of Kamlet−Taft equation. The analysis reveals that hydrogen bond donating ability (acidity) of the solvent is the most important parameter that characterizes the excited-state behavior of lumichrome. Quantum mechanical calculations using density functional theory (DFT) were done to study the most stable structure and excited-state tautomerization process of LC toward the formation of isoalloxazines. Charge localization in the excited state and formation of hydrogen-bond...

Fluorescence Solvatochromism in Lumichrome and Excited-State Tautomerization: A Combined Experimental and DFT Study

The hydrogen-bond (H-bond) donating strengths of a series of 36 hydroxylic H-bond donors (HBDs) with N-methylpyrrolidinone have been measured in CCl4 solution by FTIR spectrometry. These data allow the definition of a H-bond acidity scale named pKAHY covering almost three pK units, corresponding to 16 kJ mol–1. These results are supplemented by equilibrium constants determined in CH2Cl2 for one-third of the data set to study compounds showing a poor solubility in CCl4. A systematic comparison of these experimental results with theoretical data computed in the gas phase using DFT (density functional theory) calculations has also been carried out. Quantum electrostatic parameters appear to accurately describe the H-bond acidity of the hydroxyl group, whereas partial atomic charges according to the Merz–Singh–Kollman and CHelpG schemes are not suitable for this purpose. A substantial decrease of the H-bond acidity of the OH group is pointed out when the hydroxyl moiety is involved in intramolecular H-bond in...

Hydrogen-Bond Acidity of OH Groups in Various Molecular Environments (Phenols, Alcohols, Steroid Derivatives, and Amino Acids Structures): Experimental Measurements and Density Functional Theory Calculations

Hydrogen bond is an important type of interaction between drug molecules and their receptors. We present here a computational method for accurately predicting the hydrogen-bonding strength for different acceptors with respect to a given donor or vice versa. The method is based on quantum chemistry DFT calculation of the interaction energy between hydrogen bond donors and acceptors. An excellent linear correlation is observed between the calculated hydrogen-bonding energies and the experimentally measured hydrogen-bonding constants log Kβ on a variety of known hydrogen bond acceptors and donors. These results not only indicate the predictive power of this method but also shed light on factors that determine the magnitude of experimentally measured hydrogen-bonding constants for different acceptors with respect to a given donor, suggesting a primarily enthalpic contribution from hydrogen-bonding energy. The method can be used for evaluating the effects of steric interference and inhibitor binding geometry on hydrogen-bonding strength in drug design.

Ming-Hong Hao

Papers

Theoretical Calculation of Hydrogen-Bonding Strength for Drug Molecules