There is an important medical need for new antifungal agents with novel mechanisms of action to treat the increasing number of patients with life-threatening systemic fungal disease and to overcome the growing problem of resistance to current therapies. F901318, the leading representative of a novel class of drug, the orotomides, is an antifungal drug in clinical development that demonstrates excellent potency against a broad range of dimorphic and filamentous fungi. In vitro susceptibility testing of F901318 against more than 100 strains from the four main pathogenic Aspergillus spp. revealed minimal inhibitory concentrations of ≤0.06 μg/mLgreater potency than the leading antifungal classes. An investigation into the mechanism of action of F901318 found that it acts via inhibition of the pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase (DHODH) in a fungal-specific manner. Homology modeling of Aspergillus fumigatus DHODH has identified a predicted binding mode of the inhibitor and important interacting amino acid residues. In a murine pulmonary model of aspergillosis, F901318 displays in vivo efficacy against a strain of A. fumigatus sensitive to the azole class of antifungals and a strain displaying an azole-resistant phenotype. F901318 is currently in late Phase 1 clinical trials, offering hope that the antifungal armamentarium can be expanded to include a class of agent with a mechanism of action distinct from currently marketed antifungals.antifungal drug | Aspergillus fumigatus | mechanism of action | dihydroorotate dehydrogenase

A series of biaryl acids has been reported that inhibit both HIV-1 and HIV-2 RT, although these appear not to bind at the NNRTI site (4). NNRTIs such as nevirapine generally act as noncompetitive inhibitors of HIV-1 RT with respect to substrates (5), binding in a pocket some 10 Å from the polymerase active site (6 -8). The NNRTI binding site is contained largely within the p66 subunit of the RT heterodimer with only a few residues at the periphery of the site being contributed by the p51 subunit. The mechanism of inhibition for NNRTIs has been shown to be via a distortion of the key catalytic active site aspartyl residues (9). One series of NNRTIs previously described is the phenylethylthiazoylthiourea (PETT) series that have been shown to have potent activity against both HIV-1 virus and it's RT (10 -13). Further PETT analogues have been designed using information from the three-dimensional structure of HIV-1 RT (14 -16). In this work we report structural and biochemical studies for two members of this series referred to as PETT-1 and PETT-2 (Scheme 1).Most NNRTIs rapidly select for drug-resistant HIV-1 strains, both in tissue culture and in clinical studies, which has largely precluded their use as monotherapy (17). In contrast to the "first-generation" drugs, nevirapine and delavirdine, the so-called "second-generation" NNRTI drug, efavirenz, demonstrates resilience to the effects of certain common resistance mutations (18). However resistance to such compounds is * This work was supported by the European Commission (Project PL96-2161). The Oxford Centre for Molecular Sciences is supported by the Biotechnology and Biological Sciences Research Council, Medical Research Council, and Engineering and Physical Sciences Research Council. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.The atomic coordinates and structure factors (codes 1dtq and 1dtqsf and 1dtt and 1dttsf)

Target-focused compound libraries are collections of compounds which are designed to interact with an individual protein target or, frequently, a family of related targets (such as kinases, voltage-gated ion channels, serine/cysteine proteases). They are used for screening against therapeutic targets in order to find hit compounds that might be further developed into drugs. The design of such libraries generally utilizes structural information about the target or family of interest. In the absence of such structural information, a chemogenomic model that incorporates sequence and mutagenesis data to predict the properties of the binding site can be employed. A third option, usually pursued when no structural data are available, utilizes knowledge of the ligands of the target from which focused libraries can be developed via scaffold hopping. Consequently, the methods used for the design of target-focused libraries vary according to the quantity and quality of structural or ligand data that is available for each target family. This article describes examples of each of these design approaches and illustrates them with case studies, which highlight some of the issues and successes observed when screening target-focused libraries.

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