Throughout its known history, the gram-negative bacterium Chlamydia pneumoniae has remained a challenging target for antibacterial chemotherapy and drug discovery. Owing to its well-known propensity for persistence and recent reports on antimicrobial resistence within closely related species, new approaches for targeting this ubiquitous human pathogen are urgently needed. In this review, we des...

Knowledge of the three-dimensional structures of protein targets now emerging from genomic data has the potential to accelerate greatly drug discovery, but technical challenges and time constraints have traditionally limited their use primarily to lead optimization. Their application is now being extended beyond structure determination, into new approaches for lead discovery (for review see Blu...

Fragment-based drug design (FBDD) is considered a promising approach in lead discovery. However, for a practical application of this approach, problems remain to be solved. Hence, a novel practical strategy for three-dimensional lead discovery is presented in this work. Diverse fragments with spatial positions and orientations retained in separately adjacent regions were generated by deconstruc...

Combinatorial chemistry and parallel synthesis are important and regularly applied tools for lead identification and optimisation, although they are often accompanied by challenges related to the efficiency of library synthesis and the purity of the compound library. In the last decade, novel means of lead discovery approaches have been investigated where the biological target is actively invol...

There is a pressing, global need for new therapies for neglected diseases such as Tuberculosis, Leishmaniasis and Chagas. Traditional lead discovery approaches, while effective have not been widely applied to neglected diseases as they are expensive and time consuming. At Institut Pasteur Korea, we have developed a core technology that enables the high content screening of hundreds of thousands...

Inhibitors of the chaperone Hsp90 are potentially useful as chemotherapeutic agents in cancer. This paper describes an application of fragment screening to Hsp90 using a combination of NMR and high throughput X-ray crystallography. The screening identified an aminopyrimidine with affinity in the high micromolar range and subsequent structure-based design allowed its optimization into a low nano...

It is over 20 years since the first fragment-based discovery projects were disclosed. The methods are now mature for most 'conventional' targets in drug discovery such as enzymes (kinases and proteases) but there has also been growing success on more challenging targets, such as disruption of protein-protein interactions. The main application is to identify tractable chemical startpoints that n...

Since the late 1980s there have been striking advances, fueled by large increases in both industrial and NIHfunded academic research, that have revolutionized drug discovery. This period has seen the introduction of highthroughput screening (HTS), combinatorial chemistry, PC farms, Linux, SciFinder, structure-based design, virtual screening by docking, free-energy methods, absorption/distributi...

Several extensive small molecule screens against growing Plasmodium falciparum have recently been published [1–3] and thousands of hit structures are now publicly available. This represents a large majority of the drug-like chemical diversity currently available for screening and hence delineates the currently drugable target space of P. falciparum, since the ‘‘drugability’’ term includes an ‘‘...