Protein targets, hydrogen bonding interactions

Finally, dynamic structure-based pharmacophore models can be derived through a method first described by Carlson et al that uses multiple conformations of the target protein, which are obtained either by molecular dynamics simulation or by the use of multiple experimentally determined conformations. The binding sites of the respective snapshots are flooded with small molecular probes (e.g., methanol for hydrogen-bond interactions and benzene for aromatic hydrophobic interactions) and while the protein structure is held rigid the probe molecules are subjected to a low-temperature Monte Carlo minimization where they undergo multiple, simultaneous gas-phase... 

Fig. 9 Fragment evolution for the target CDK2 as described in the text Key hydrogen bonding interactions with the protein are denoted by dashed lines...

As we have just seen, the initial encounter complex between an enzyme and its substrate is characterized by a reversible equilibrium between the binary complex and the free forms of enzyme and substrate. Hence the binary complex is stabilized through a variety of noncovalent interactions between the substrate and enzyme molecules. Likewise the majority of pharmacologically relevant enzyme inhibitors, which we will encounter in subsequent chapters, bind to their enzyme targets through a combination of noncovalent interactions. Some of the more important of these noncovalent forces for interactions between proteins (e.g., enzymes) and ligands (e.g., substrates, cofactors, and reversible inhibitors) include electrostatic interactions, hydrogen bonds, hydrophobic forces, and van der Waals forces (Copeland, 2000). 

The hydroxyl radical is a small, highly reactive probe that is formed in water and primarily targets hydrophobic residues [109]. This may be an ideal probe for protein-protein interactions because tyrosine, tryptophan and phenylalanine are most likely to be found at an interface [110, 111]. Although protein-DNA interfaces are comprised of charged and hydrogen-bond donor side-chains, even these residues may be probed by hydroxyl radicals [112]. 

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