Hydrogen-Bond Donors in Drug Design

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.

“Magic Chloro”: Profound Effects of the Chlorine Atom in Drug Discovery

“…Although alkyl chlorides have been found to be much less genotoxic than alkyl bromides or alkyl sulfonates, primary alkyl chlorides were found to be genotoxic in vapor-phase exposure experiments . At the other end of the spectrum, tertiary alkyl chlorides are much less reactive and can be used as advantageous bioisosteres of a t -butyl group. , Secondary alkyl chlorides should be incorporated into lead compounds with some caution although these motifs have been installed in drugs (as exemplified by 43 and 44 ) and a recent article has highlighted their underexplored nature in medicine . As is the case for any drug candidate, metabolic stability and off-target toxicity must always be evaluated, since any substituent can potentially present issues in preclinical studies; even seemingly “safe” and oft-used substituents such as fluorine can present unwanted effects …”

“… Although the Topliss tree scheme can be beneficial and para -chlorinated phenyl building blocks are typically easier to purchase or to synthesize, medicinal chemists should try to avoid the “ para -chlorophenyl bias” and treat this topology more holistically since it really does not offer a particularly privileged status. As a consequence of (3) above, the organic chemistry community should, in turn, develop more ortho - and meta -chlorination methodologies to help medicinal chemists synthesize compounds that should be created from the point of view of exploring a protein–ligand interaction, rather than preparing compounds that are the easiest to create. Aliphatic chlorides, especially tertiary alkyl chlorides and perhaps secondary alkyl chlorides, can be beneficial and should not be disregarded entirely due to preconceived notions of toxicity associated with the potential for covalent reactivity. Nevertheless, the deployment of alkyl chlorides needs to be judicious in nature and there may be circumstances where such motifs could be advantageous. , The scientific data generated with a molecule (e.g., pharmacokinetic parameters, toxicology results) should always be followed for guidance, just like for any other lead compound moving forward in preclinical studies. Chlorination should not be overused as a molecular editing strategy if the lipophilicity of a compound is already high, and aqueous solubility is compromised. In such a case, the introduction of additional chlorine atoms may render a molecule difficult to formulate.…”

Construction of targeted 10B delivery agents and their uptake in gastric and pancreatic cancer cells

“…The coordination between nitrogen atom and boron atom is due to the lack of electron property of boron atom, while boric acid will form ester with amino acid end. These processes will lose the proton, which will reduce the molecular polarity to a certain extent ( 32 , 33 ). It is obvious that the elimination of active protons will affect its solubility.…”

Natural Lipid Extracts as an Artificial Membrane for Drug Permeability Assay: In Vitro and In Silico Characterization

“…The partial tissue-specific function of N HBA cannot be examined independently of the Spearman correlation pattern found in N HBD . Similar to Lipinski’s Ro5 (N HBA ≤ 10, N HBD ≤ 5) [ 16 ], N HBA /N HBD balance suggests an, e.g., better aqueous solubility (N HBA N HBD ) [ 41 ], BBB permeability (N HBD N HBA ) [ 42 ], reduction in P-glycoprotein efflux ratio (at lower N HBD ) [ 43 ], and biological target recognition [ 44 ], which is related to the HBD acidity and HBA basicity nature [ 45 , 46 ], and that the greater polarity and solvation of drug-like compounds is ensured by the greater presence of HBA on the molecular surface [ 47 ]. This HBD–HBA imbalance frustration can also be identified by the data pairs of significant negative correlations for N HBA —LTLE-specific and N HBD —brain-lipid-specific permeability.…”