Euodenine A: a small-molecule agonist of human TLR4.

A small-molecule natural product, euodenine A (1), was identified as an agonist of the human TLR4 receptor. Euodenine A was isolated from the leaves of Euodia asteridula (Rutaceae) found in Papua New Guinea and has an unusual U-shaped structure. It was synthesized along with a series of analogues that exhibit potent and selective agonism of the TLR4 receptor. SAR development around the cyclobutane ring resulted in a 10-fold increase in potency. The natural product demonstrated an extracellular site of action, which requires the extracellular domain of TLR4 to stimulate a NF-κB reporter response. 1 is a human-selective agonist that is CD14-independent, and it requires both TLR4 and MD-2 for full efficacy. Testing for immunomodulation in PBMC cells shows the induction of the cytokines IL-8, IL-10, TNF-α, and IL-12p40 as well as suppression of IL-5 from activated PBMCs, indicating that compounds like 1 could modulate the Th2 immune response without causing lung damage.

Learning lessons from drugs that have recently entered the market.

Which projects in the drug discovery field are most likely to be successful? In this article, I provide guidelines for answering this question by examining recent drug market entrants in detail, in particular their route of administration, trial design, novelty, therapeutic target and toxicities. I identify targets, trials and organizations as the key issues that are currently leading to the poor productivity in the pharmaceutical industry. Here, I outline some solutions and reasons for optimism, and suggest that the key determinants for success in drug discovery can be defined by studying recently launched drugs.

Synthesis of heavily substituted 2-aminopyridines by displacement of a 6-methylsulfinyl group.

2-Aminopyridines, with a variety of polar 6-substituents, were elaborated by displacement of a methylsulfinyl group from the 6-position of the pyridine ring. The requisite 6-thiomethyl pyridines were synthesized by reaction of 2-(1-phenylethylidene)propanedinitriles with dimethyl N-cyanodithioiminocarbonate.

Discovery of potent CRTh2 (DP2) receptor antagonists.

Starting with the weak agonist indomethacin, a series of potent, selective CRTh2 (DP(2)) antagonists have been discovered as potential treatments for asthma, allergic rhinitis and other inflammatory diseases.

Implications of protein flexibility for drug discovery.

Proteins are in constant motion between different conformational states with similar energies. This has often been ignored in drug design. However, protein flexibility is fundamental to understanding the ways in which drugs exert biological effects, their binding-site location, binding orientation, binding kinetics, metabolism and transport. Protein flexibility allows increased affinity to be achieved between a drug and its target. This is crucial, because the lipophilicity and number of polar interactions allowed for an oral drug is limited by absorption, distribution, metabolism and toxicology considerations.

Application and limitations of X-ray crystallographic data in structure-based ligand and drug design.

Structure-based design usually focuses upon the optimization of ligand affinity. However, successful drug design also requires the optimization of many other properties. The primary source of structural information for protein-ligand complexes is X-ray crystallography. The uncertainties introduced during the derivation of an atomic model from the experimentally observed electron density data are not always appreciated. Uncertainties in the atomic model can have significant consequences when this model is subsequently used as the basis of manual design, docking, scoring, and virtual screening efforts. Docking and scoring algorithms are currently imperfect. A good correlation between observed and calculated binding affinities is usually only observed only when very large ranges of affinity are considered. Errors in the correlation often exceed the range of affinities commonly encountered during lead optimization. Some structure-based design approaches now involve screening libraries by using technologies based on NMR spectroscopy and X-ray crystallography to discover small polar templates, which are used for further optimization. Such compounds are defined as leadlike and are also sought by more traditional high-throughput screening technologies. Structure-based design and HTS technologies show important complementarity and a degree of convergence.

Hydrogen Bonding, Hydrophobic Interactions, and Failure of the Rigid Receptor Hypothesis.

Why does experimental determination of the structure of drug-receptor complexes so often result in surprises? The importance of hydrogen bonding and hydrophobic interactions in drug receptor binding is discussed. Hydrophobic interactions receive too little consideration from most molecular modeling packages. Their role in the failure of the rigid receptor hypothesis and the implications for drug design are considered.