Optimization of Small Molecule Drugs Binding to Highly Polar Target Sites: Lessons from the Discovery and Development of Neuraminidase Inhibitors

Abstract

Binding affinity optimization of small molecules interacting with polar binding sites on target proteins is a formidable, but not uncommon challenge in drug discovery. The challenge relates to the difficulty of integrating favourable and unfavourable polar, non-polar and conformation contributions into overall favourable binding energies. This review describes the surprising breakthrough findings leading to the development of Tamiflu, a clinically efficacious orally bioavailable drug targeting the active site of influenza neuraminidase (NA). The NA active site is highly polar and formed mostly by arginine, aspartate and glutamate residues. This active site structure evolved for efficient interaction with charged sialic acid moieties on glycoproteins and stabilization of an oxocarbonium ion in the transition state of the neuraminidase reaction. The initial strategy of optimizing polar interactions in transition state analogs led to NA inhibitors (NAIs) with sub-nanomolar binding affinities, but such compounds were highly polar and lacked oral bioavailability. The realization of the possibility to achieve high affinity binding in a highly polar active site through optimization of non-polar and van-der-Waals interactions initially appeared counterintuitive and required a few serendipitous findings, but was key to reduce the polarity of drug candidates, avoid large desolvation penalties and achieve oral bioavailability.

Advances on the compositional analysis of glycosphingolipids combining thin-layer chromatography with mass spectrometry

“…However, understanding the means by which pathogens exploit rafts might lead to new therapeutic strategies to prevent or alleviate certain infectious diseases. Thus, the microbe-host interface is currently in focus because of attempts to develop infection therapy in humans based on either natural receptor saccharide (respiratory and gastrointestinal diseases) (Karlsson, 1998;Sharon & Ofek, 2000;Sharon, 2006) or sophisticated multivalent sialyloligosaccharides-based influenza virus adhesion inhibition strategies (Klumpp & Graves, 2006;Sun, 2007).…”

Potential Targets and Their Relevant Inhibitors in Anti-influenza Fields

“…As a potent and long-acting NAI, dimeric zanamivir (41) could provide effective treatment and prophylaxis for influenza virus infections at a once-weekly dosing regimen [191,192]. Recent lessons from the discovery and development of NAIs have been reviewed in several papers elsewhere [20,[193][194][195][196]. influenza A virus NA could be divided into two distinct families: group 1 (N1, N4, N5, and N8 subtypes) and group 2 (N2, N3, N6, N7, and N9 subtypes).…”

Strategies of Development of Antiviral Agents Directed Against Influenza Virus Replication

“…Lessons from the discovery and development of NA inhibitors (NAIs) have been thoroughly reviewed recently [10,12]. The success of Tamiflu and Relenza represents important milestones for the drug discovery area.…”

“…The historical accounts of drug discovery against influenza virus have been addressed recently by several recent reviews [9][10][11][12][13]. In this article, in addition to updating the progress of drug discovery against influenza virus replication, we also discuss the potential new targets and efforts towards identification of novel targets along the virion assembly and maturation pathway.…”