Non-covalent molecular interactions in an aqueous environment and the resulting Gibbs free energy of binding are what drive molecular recognition between a drug candidate and target protein. The selection of which amino acid functionality to target and which ligand functionality to use to form molecular interactions that result in sufficient binding affinity and selectivity for a drug represents the key task of early drug design.
The Protein Database (PDB) has allowed the analysis of over 10,000 protein-ligand complexes which consist of almost one million atom pairs within less than 4 A proximity of each other by de Freitas and Schapira in 2017. These interactions can be categorized into six molecular interaction classes.
- Hydrogen Bonds – 79%
- pi-pi Interactions – 8%
- sigma-sigma interactions – 6%
- cation-pi interactions – 2%
- sigma hole bonds – 0.3%
- pi-hole bonds -0.1%
de Freitas applied a different categorization (he used seven classes) than I have here. I have deviated from de Freitas’ categorization because he combined a number of different types of weak molecular interactions under the category called “hydrophobic interactions”. I have separated these interactions out, for example CH-pi interactions are a type of H-bond and sigma-sigma interactions is the name I have chosen for aliphatic CH groups interacting with each other.
hydrogen bonds
Hydrogen bonds are by far the most frequent molecular interaction used in drug design, representing almost 80% of all the interactions in the de Freitas analysis. Hence, obtaining a understanding of how H-bonds work in aqueous solution should be at the top of the list for any budding molecular designer. The hydrogen donor moiety of the H-bond is a hydrogen atom attached to an element more electronegative than hydrogen which forms a non-covalent bond with an electron rich region (i.e. lone pair or pi system) of another molecule (inter-molecular) or with the same molecule (intra-molecular).
H-bonds come in many facets and while I have chosen to apply a broad definition here, there are three sub-classifications which are important to note. Classical H-bonds refer to systems where X = N, O or S and Y is a lone pair. Weak H-bonds are formed when CH groups represent the H-bond donor. H-bonds can also be charged, either with one charge (positively charged donor or negatively charged acceptor – these can be called charged assisted H-bonds) or doubly charged (positively charged donor and negatively charged acceptor) which are typically called salt-bridges.
- Charged H-Bonds
- Classical H-Bonds (neutral)
- Weak H-Bonds or CH H-Bonds
beware of the bias
The more efficient student might postulate that designing drugs solely with H-bonds could be sufficient given that they suffice Pareto’s 80% rule. It would certainly save a lot of time reading about how pi-pi, sigma-sigma, cation-pi, sigma hole and pi hole interactions work. While it could be argued that the protein side molecular interactions is unbiased due to evolution, the ligand side is clearly influenced by the biases of medicinal chemists past (the use of halogen bonding, a sigma hole interaction, is a good example of this). Hence, one should be careful to conclude that low historical interaction frequency means less utility in drug design. There will be many future posts on all six molecular interactions and their application to drug design.
