A Medicinal Chemist’s Guide to Molecular Interactions

By C. Bissantz, Bernd Kuhn, M. Stahl. 2010

1,485 citations recorded by the source corpus.

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.

Subfields: Organic Chemistry, Physical and Theoretical Chemistry, Computational Chemistry & Drug Discovery

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Citations in the corpus

A Role for Fragment-Based Drug Design in Developing Novel Lead Compounds for Central Nervous System Targets (2015, background): “Nevertheless, a crystal structure is a static representation of a protein and cannot account for the multiple conformational states within the protein–ligand complex (14).”
Molecular Docking and Structure-Based Drug Design Strategies (2015, background): “…the use of such algorithms, a comparison between structural water in multiple crystal structures should be carried out to minimize the risk of mistakenly discarding or keeping a specific water molecule [109] (strongly bound water is often conserved across multiple crystallographic structures).”
AtomNet: A Deep Convolutional Neural Network for Bioactivity Prediction in Structure-based Drug Discovery (2015, background): “When chemical groups interact, e.g. through hydrogen bonding or π -bond stacking, the strength of their repulsion or attraction may vary with their type, distance, and angle, but these are predominantly local effects [8].”
The enumeration of chemical space (2012, background): “Virtual screening can be performed either on the basis of comparisons with already existing active molecules (ligand based), 27 , 28 or by using information from the biological system, usually the three-dimensional structure of the protein to which the molecules should bind (target based).”
A very short history of structure-based design: how did we get here and where do we need to go? (2011, background): “Sadly, high-resolution X-ray crystal structures don’t identify the strength of each interaction! Our ability to predict which molecules to synthesize next remains empirical, guided by these observations of preferred noncovalent interactions and supplemented with qualitative docking and other calcula”
A practical guide to large-scale docking (2021, background): “Therefore, we suggest keeping the number of unsatis ﬁ ed acceptors below 3 and the number of unsatis ﬁ ed donors to 1 or below, as burying a donor can incur a greater penalty than burying an acceptor 133”
Regulation of protein-ligand binding affinity by hydrogen bond pairing (2016, background): “Aromatic rings are weak H-bond acceptors (32, 34), whereas CH groups are weak H-bond donors (34, 35).”