AI Article Synopsis
- Hydrogen-bond donors create more challenges for drug designers compared to hydrogen-bond acceptors, which are usually more numerous and have greater polarity in drug-like compounds.
- The polarity imbalance affects the optimization of drug permeability and solubility, with the presence of hydrogen-bond donors often indicating the existence of hydrogen-bond acceptors.
- The text also explores issues like frustrated solvation and electrostatic interactions from aligned hydrogen-bond donors and acceptors, comparing various types of hydrogen-bond donors and introducing alternatives like halogen and chalcogen-bond donors.
Article Abstract
Hydrogen-bond donors are seen to cause more problems for drug designers than hydrogen-bond acceptors. Most of the polarity in drug-like compounds comes from hydrogen-bond acceptors since they typically exceed the hydrogen-bond donors in number and are more heavily solvated on an individual basis. The implications of this polarity imbalance for optimization of permeability and aqueous solubility are discussed. A factor that should be considered in optimization of ligand recognition by targets is that the presence of a hydrogen-bond donor generally implies that a hydrogen-bond acceptor is also present (but not vice versa). Frustrated solvation and secondary electrostatic interactions result from aligned hydrogen-bond donors and acceptors, and the design opportunities presented by these phenomena are discussed. Hydrogen-bond donors based on oxygen, nitrogen and carbon are compared as target recognition elements, and halogen- and chalcogen-bond donors are discussed as hydrogen-bond donor equivalents.
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| http://dx.doi.org/10.1021/acs.jmedchem.2c01147 | DOI Listing |
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