Target-based drug discovery for the development of novel antiinfectives

Selzer, Paul M.; Brutsche, Sandra; Wiesner, Petra; Schmid, Peter; Müllner, Hubert

doi:10.1016/s1438-4221(00)80090-9

Cited by 27 publications

(14 citation statements)

References 49 publications

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“…Potential lead compounds against these targets can be identified from high-throughput screening (HTS) campaigns or through ligand- and structure-based design methods. 2 …”

mentioning

confidence: 99%

Structure–activity relationships of compounds targeting mycobacterium tuberculosis 1-deoxy-d-xylulose 5-phosphate synthase

Mao

Eoh

et al. 2008

Bioorganic & Medicinal Chemistry Letters

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We report on a target-based approach to identify possible Mycobacterium tuberculosis DXS inhibitors from the structure of a known transketolase inhibitor. A small focused library of analogs was assembled in order to begin elucidating some meaningful structure–activity relationships of 3-(4-chloro-phenyl)-5-benzyl-4H-pyrazolo[1,5-a]pyrimidin-7-one. Ultimately we found that 2-methyl-3-(4-fluorophenyl)-5-(4-meth-oxy-phenyl)-4H-pyrazolo[1,5-a]pyrimidin-7-one, although still weak, was able to inhibit M. tuberculosis DXS with an IC50 of 10.6 μM.

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“…Potential lead compounds against these targets can be identified from high-throughput screening (HTS) campaigns or through ligand- and structure-based design methods. 2 …”

mentioning

confidence: 99%

Structure–activity relationships of compounds targeting mycobacterium tuberculosis 1-deoxy-d-xylulose 5-phosphate synthase

Mao

Eoh

et al. 2008

Bioorganic & Medicinal Chemistry Letters

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“…Once a putative target has been identified by these means the challenge is to find a substance interfering with this enzyme or pathway, ideally using a parasite-based screen (see [123] and references therein). More likely, however, will be the initial screening of chemical libraries with the recombinant protein to identify active lead compounds [129][130][131] and the subsequent verification of candidate substances for activity in the whole parasite system. Instrumental for this latter approach are high-throughput screens to validate both, the target and the compound.…”

Section: Current Drug Screening Methods For Apicomplexamentioning

confidence: 99%

Biosynthetic Pathways of Plastid-Derived Organelles as Potential Drug Targets Against Parasitic Apicomplexa

Seeber

2003

curr drug targets immune endocr metabol disord

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Apicomplexan parasites are a large phylum of unicellular and obligate intracellular organisms of great medical importance. They include the human pathogens Plasmodium spp., the causative agent of malaria, and Toxoplasma gondii, an opportunistic parasite of immunosuppressed individuals and a common cause of congenital disease, together affecting several hundred million people worldwide. The search for new and effective drugs against these pathogens has been boosted during the last years by an unexpected finding. Through molecular and cell biological analysis it was realized that probably most members of this phylum harbor a plastid-like organelle, called the apicoplast, which probably is derived from the engulfment of a red alga in ancient times. Although the apicoplast itself contains a small circular genome, most of the proteome of this organelle is encoded in the nuclear genome, and the proteins are subsequently transported to the apicoplast. It is assumed to contain a number of unique metabolic pathways not found in the vertebrate host, making it an ideal "playground" for those interested in drug targets. Recent reports have shown that the rationale of this approach is valid and that new drugs which are urgently needed especially for plasmodial infections, might be developed in the near future based on these targets. Amongst them are three enzymes of the plant-like fatty acid synthesis machinery and enzymes of the non-mevalonat isoprenoid biosynthesis pathway. From their presence in the apicoplast it can be concluded that fatty acid and lipid biosynthesis seems to be a major function of the apicoplast. Another recently described apicoplast enzyme, ferredoxin-NADP(+)-reductase and its redox partner, ferredoxin, points to another interesting organelle-specific biosynthetic pathway, namely [Fe-S] cluster biosynthesis. In the present review, the fundamental aspects of the apicoplast as drug target will be described, together with the specific pathways and their currently known inhibitors. Furthermore, based on the recent findings potentially new targets will be discussed. A short overview of the presently available high-throughput methods for Apicomplexa to evaluate the potency of new inhibitory substances will also be given.

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“…Establishing and screening a small molecule collection using high‐throughput screening (HTS) methods was, until recently, only feasible in pharmaceutical companies. However, as access to collections and HTS technology has improved (Selzer et al. , 2000), the academic research community has become increasingly interested in these approaches (Gura, 2000).…”

Section: What Is Required?mentioning

confidence: 99%

Using small molecules to study big questions in cellular microbiology

2002

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Summary High‐throughput screening of small molecules is used extensively in pharmaceutical settings for the purpose of drug discovery. In the case of antimicrobials, this involves the identification of small molecules that are significantly more toxic to the microbe than to the host. Only a small percentage of the small molecules identified in these screens have been studied in sufficient detail to explain the molecular basis of their antimicrobial effect. Rarer still are small molecule screens undertaken with the explicit goal of learning more about the biology of a particular microbe or the mechanism of its interaction with its host. Recent technological advances in small molecule synthesis and high‐throughput screening have made such mechanism‐directed small molecule approaches a powerful and accessible experimental option. In this article, we provide an overview of the methods and technical requirements and we dis‐cuss the potential of small molecule approaches to address important and often otherwise experimentally intractable problems in cellular microbiology.

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Target-based drug discovery for the development of novel antiinfectives

Cited by 27 publications

References 49 publications

Structure–activity relationships of compounds targeting mycobacterium tuberculosis 1-deoxy-d-xylulose 5-phosphate synthase

Structure–activity relationships of compounds targeting mycobacterium tuberculosis 1-deoxy-d-xylulose 5-phosphate synthase

Biosynthetic Pathways of Plastid-Derived Organelles as Potential Drug Targets Against Parasitic Apicomplexa

Using small molecules to study big questions in cellular microbiology

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