Discovery of Potent and Selective Leads against <i>Toxoplasma gondii</i> Dihydrofolate Reductase via Structure-Based Design

Welsch, Matthew; Jian, Zhou; Gao, Yueqiang; Yan, Yunqing; Porter, Gene; Agnihotri, Gautam; Li, Yingjie; Lu, Henry Horng Shing; Chen, Zhongguo; Thomas, Stephen B.

doi:10.1021/acsmedchemlett.6b00328

Cited by 26 publications

(28 citation statements)

References 25 publications

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“…Recently, researchers reported that computational analysis of biochemical differences between human and T. gondii dihydrofolate reductase enabled the design of inhibitors with both improved potency and selectivity against T. gondii (Welsch et al, 2016). El-Zawawy et al reported that incorporating triclosan into in the lipid bilayer of liposomes allowed its use in lower doses, which in turn, reduced its biochemical adverse effects (El-Zawawy et al, 2015b).…”

Section: Discussionmentioning

confidence: 99%

A Systematic Review of In vitro and In vivo Activities of Anti-Toxoplasma Drugs and Compounds (2006–2016)

et al. 2017

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The currently available anti-Toxoplasma agents have serious limitations. This systematic review was performed to evaluate drugs and new compounds used for the treatment of toxoplasmosis. Data was systematically collected from published papers on the efficacy of drugs/compounds used against Toxoplasma gondii (T. gondii) globally during 2006–2016. The searched databases were PubMed, Google Scholar, Science Direct, ISI Web of Science, EBSCO, and Scopus. One hundred and eighteen papers were eligible for inclusion in this systematic review, which were both in vitro and in vivo studies. Within this review, 80 clinically available drugs and a large number of new compounds with more than 39 mechanisms of action were evaluated. Interestingly, many of the drugs/compounds evaluated against T. gondii act on the apicoplast. Therefore, the apicoplast represents as a potential drug target for new chemotherapy. Based on the current findings, 49 drugs/compounds demonstrated in vitro half-maximal inhibitory concentration (IC50) values of below 1 μM, but most of them were not evaluated further for in vivo effectiveness. However, the derivatives of the ciprofloxacin, endochin-like quinolones and 1-[4-(4-nitrophenoxy) phenyl] propane-1-one (NPPP) were significantly active against T. gondii tachyzoites both in vitro and in vivo. Thus, these compounds are promising candidates for future studies. Also, compound 32 (T. gondii calcium-dependent protein kinase 1 inhibitor), endochin-like quinolones, miltefosine, rolipram abolish, and guanabenz can be repurposed into an effective anti-parasitic with a unique ability to reduce brain tissue cysts (88.7, 88, 78, 74, and 69%, respectively). Additionally, no promising drugs are available for congenital toxoplasmosis. In conclusion, as current chemotherapy against toxoplasmosis is still not satisfactory, development of well-tolerated and safe specific immunoprophylaxis in relaxing the need of dependence on chemotherapeutics is a highly valuable goal for global disease control. However, with the increasing number of high-risk individuals, and absence of a proper vaccine, continued efforts are necessary for the development of novel treatment options against T. gondii. Some of the novel compounds reviewed here may represent good starting points for the discovery of effective new drugs. In further, bioinformatic and in silico studies are needed in order to identify new potential toxoplasmicidal drugs.

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Section: Discussionmentioning

confidence: 99%

A Systematic Review of In vitro and In vivo Activities of Anti-Toxoplasma Drugs and Compounds (2006–2016)

et al. 2017

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“…As T. gondii is incapable of salvaging thymidine from the host, DHFR inhibition leads to indirect inhibition of TS, but the direct inhibition of TS would logically be preferred . Differences in amino acid sequences and structures of human and T. gondii DHFR have paved the way for the selective inhibition of these enzymes, whereas the considerable homology between TS of the parasite and human makes the design of selective inhibitors of the TS difficult . Antibiotic resistance is also a challenging and growing public health problem, threatening the effective prevention and treatment of infections .…”

Section: Introductionmentioning

confidence: 99%

Proteochemometric modeling of the origin of thymidylate synthase inhibition

Rasti

Shahangian

2018

Chem Biol Drug Des

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Due to its crucial role in DNA synthesis, thymidylate synthase (TS) has been considered as a potential therapeutic target. Inhibition of the enzyme is a promising strategy for the treatment of some hyperproliferative diseases, including infections. As TS species-specific inhibitors would be able to distinguish between the host and the pathogens, developing highly selective inhibitors is of great clinical importance. TS is among the most highly conserved enzymes over evolutionary history, making the design of its species-selective inhibitor significantly challenging. The chemical interaction space, governed by a set of non-selective TS inhibitors, has been explored for human TS and its homologous proteins in both Toxoplasma gondii and Escherichia coli using proteochemometrics modeling (PCM). Validity, robustness, and prediction power of the PCM model have been assessed applying a diverse set of internal/external validation approaches. Our PCM model has provided major structural information, which is indeed of great help to design new TS species-specific inhibitors with the simultaneous inhibition ability toward both T. gondii and E. coli. To show applicability of the PCM model, new compounds have been designed based on structural information provided by the constructed model. Final results have been very promising with regard to selectivity ratios of the designed compounds for different TS isoforms, confirming the applicability of the PCM model.

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“…T. gondii is an obligate cosmopolitan apicomplexan intracellular parasite which affects more than one‐third of the world population . Infection by T. gondii causes the worldwide disease toxoplasmosis .…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, the parasite creates a wide spectrum of disease, especially in congenital toxoplasmosis that causes serious fetal malformation during pregnancy . Acute toxoplasmosis can also be seen in immunocompromised patients . T. gondii utilizes a bifunctional form of the fusion enzyme dihydrofolate reductase‐thymidylate synthase (DHFR‐TS) for folate metabolism and pyrimidine biosynthesis pathway.…”

Section: Introductionmentioning

confidence: 99%

“…Dual functionality accelerates metabolic processing and is essential for cellular growth and proliferation. These characteristics make protozoan DHFR‐TS an attractive target for pharmacologic intervention . A few numbers of medications available for the treatment of toxoplasmosis show several limitations, including drug intolerance, low bioavailability, high toxicity, and drug resistance developed by the parasite.…”

Section: Introductionmentioning

confidence: 99%

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Probing the origin of dihydrofolate reductase inhibition via proteochemometric modeling

Hariri

Ghasemi

Shirini

et al. 2018

Journal of Chemometrics

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Dihydrofolate reductase (DHFR) is an essential enzyme in the folate metabolism pathway and an important target of antineoplastic, antimicrobial, antiprotozoal, and antiinflammatory drugs. Despite the clinical effectiveness of current antifolate treatments, new drugs are needed to be designed due to developing resistance of this enzyme through multiple‐site mutagenesis. Understanding the factors affecting the ligand binding selectivity profiles among DHFR families is critical for the design of novel potent and selective inhibitors, with the least side effects, against DHFR of pathogens. Hybrid scaffolds containing pyrimidine ring are effective in DHFR inhibition. In this study, using proteochemometric (PCM) modeling, we designed and evaluated new potent pyrimidine scaffold‐based inhibitors via 3‐dimensional alignment‐free GRid‐INdependent Descriptors (GRIND), VolSurf molecular, and sequence‐based (z‐scale) descriptors to provide ligand and receptor descriptors, respectively. Validation and robustness of the model were confirmed by venetian blinds cross‐validation and Y‐scrambling approaches, respectively. Applicability domain (AD) analysis was performed to estimate the likelihood of reliable prediction for compounds. To show the applicability of the PCM model, new ligands were designed using structural data retrieved from this model. Inhibitory activities of the designs were then predicted, and selectivity ratio profiles were investigated. Finally, potent and highly selective inhibitors were identified regarding the protozoan parasite Toxoplasma gondii, followed by evaluating the ADMET parameters of the ligands.

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Discovery of Potent and Selective Leads against Toxoplasma gondii Dihydrofolate Reductase via Structure-Based Design

Cited by 26 publications

References 25 publications

A Systematic Review of In vitro and In vivo Activities of Anti-Toxoplasma Drugs and Compounds (2006–2016)

A Systematic Review of In vitro and In vivo Activities of Anti-Toxoplasma Drugs and Compounds (2006–2016)

Proteochemometric modeling of the origin of thymidylate synthase inhibition

Probing the origin of dihydrofolate reductase inhibition via proteochemometric modeling

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