Kinases and kinase inhibitors

Patrick, Graham L.; Turner, Helen

doi:10.1016/b978-0-08-101210-9.00013-5

Cited by 3 publications

(3 citation statements)

References 54 publications

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“…The most active analog, phenylurea, exhibited an EC 50 of 28 nM but was reported to be a weak inhibitor of Pf TMPK with a binding affinity of 200 µM ( Cui et al., 2012 ; Chen et al., 2018 ). It was also observed that ureas showed more antimalarial activities than thioureas ( Cui et al., 2012 ; Patrick and Turner, 2020 ).…”

Section: Introductionmentioning

confidence: 98%

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Targeting the Plasmodium falciparum’s Thymidylate Monophosphate Kinase for the Identification of Novel Antimalarial Natural Compounds

Enninful

Kwofie

Tetteh-Tsifoanya

et al. 2022

Front. Cell. Infect. Microbiol.

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Recent reports of resistance to artemisinin-based combination drugs necessitate the need to discover novel antimalarial compounds. The present study was aimed at identifying novel antimalarial compounds from natural product libraries using computational methods. Plasmodium falciparum is highly dependent on the pyrimidine biosynthetic pathway, a de novo pathway responsible for the production of pyrimidines, and the parasite lacks the pyrimidine salvage enzymes. The P. falciparum thymidylate monophosphate kinase (PfTMPK) is an important protein necessary for rapid DNA replication; however, due to its broad substrate specificity, the protein is distinguished from its homologs, making it a suitable drug target. Compounds from AfroDB, a database of natural products originating from Africa, were screened virtually against PfTMPK after filtering the compounds for absorption, distribution, metabolism, excretion, and toxicity (ADMET)-acceptable compounds with FAF-Drugs4. Thirteen hits with lower binding energies than thymidine monophosphate were selected after docking. Among the thirteen compounds, ZINC13374323 and ZINC13365918 with binding energies of −9.4 and −8.9 kcal/mol, respectively, were selected as plausible lead compounds because they exhibited structural properties that ensure proper binding at the active site and inhibitory effect against PfTMPK. ZINC13374323 (also called aurantiamide acetate) is known to exhibit anti-inflammatory and antiviral activities, and ZINC13365918 exhibits antileishmanial activity. Furthermore, aurantiamide acetate, which is commercially available, is a constituent of Artemisia annua, the herb from which artemisinin was derived. The compound also shares interactions with several residues with a potent thymidine analog inhibitor of PfTMPK. The anti-plasmodial activity of aurantiamide acetate was evaluated in vitro, and the mean half-maximal inhibitory concentration (IC50) was 69.33 μM when synchronized P. falciparum 3D7 culture was used as compared to IC50 > 100 μM with asynchronized culture. The significance of our findings within the context of malaria treatment strategies and challenges is discussed.

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Section: Introductionmentioning

confidence: 98%

“…So far, thiourea has been shown to exhibit inhibitory activity against Pf TMPK, the compound that was first discovered to inhibit the TMPK of Mycobacterium tuberculosis ( Mt TMPK) ( Cui et al., 2012 ; Patrick and Turner, 2020 ). The inhibitory effect of thiourea on Pf TMPK is however weaker than that of Mt TMPK.…”

Section: Introductionmentioning

confidence: 99%

Targeting the Plasmodium falciparum’s Thymidylate Monophosphate Kinase for the Identification of Novel Antimalarial Natural Compounds

Enninful

Kwofie

Tetteh-Tsifoanya

et al. 2022

Front. Cell. Infect. Microbiol.

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“…Finally, M5717 (DDD107498) is a quinoline derivative showing multistage activity ( 20 ) through the inhibition of the translocation factor eukaryotic elongation factor 2 (eEF2) and has reached phase I studies. Regarding the promising molecules that are studied at a preclinical stage, it appears that plasmodial kinases are quite promising targets ( 21 , 22 ), as recently demonstrated by van der Watt et al in the search for novel gametocytocidal compounds ( 23 ) or by Alam et al, who identified the P. falciparum cyclin-dependent-like protein kinase 3 ( Pf CLK3) as a main drug target for developing novel multistage antimalarial drugs ( 24 ). In 2015, our group reported that a new compound from a chemical library containing kinase inhibitor candidates and belonging to the thienopyrimidinone series was active in vitro toward the blood stage of P. falciparum (50% effective concentration [EC 50 ] =35 to 200 nM) and the liver stage of Plasmodium yoelii (EC 50 = 35 nM) parasites infecting HepG2-CD81 cells ( 25 ).…”

Section: Introductionmentioning

confidence: 99%

A New Thienopyrimidinone Chemotype Shows Multistage Activity against Plasmodium falciparum, Including Artemisinin-Resistant Parasites

et al. 2021

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This work reports a new chemical structure that (i) displays activity against the human malaria parasite Plasmodium falciparum at 3 stages of the parasitic cycle (blood stage, hepatic stage, and sexual stages), (ii) remains active against parasites that are resistant to the first-line treatment recommended by the World Health Organization (WHO) for the treatment of severe malaria (artemisinins), and (iii) reduces transmission of the parasite to the mosquito vector in a mouse model. This new molecule family could open the way to the conception of novel antimalarial drugs with an original multistage mechanism of action to fight against Plasmodium drug resistance and block interhuman transmission of malaria.

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Bioactive Compounds from Marine Sponges: Fundamentals and Applications

et al. 2021

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Marine sponges are sessile invertebrates that can be found in temperate, polar and tropical regions. They are known to be major contributors of bioactive compounds, which are discovered in and extracted from the marine environment. The compounds extracted from these sponges are known to exhibit various bioactivities, such as antimicrobial, antitumor and general cytotoxicity. For example, various compounds isolated from Theonella swinhoei have showcased various bioactivities, such as those that are antibacterial, antiviral and antifungal. In this review, we discuss bioactive compounds that have been identified from marine sponges that showcase the ability to act as antibacterial, antiviral, anti-malarial and antifungal agents against human pathogens and fish pathogens in the aquaculture industry. Moreover, the application of such compounds as antimicrobial agents in other veterinary commodities, such as poultry, cattle farming and domesticated cats, is discussed, along with a brief discussion regarding the mode of action of these compounds on the targeted sites in various pathogens. The bioactivity of the compounds discussed in this review is focused mainly on compounds that have been identified between 2000 and 2020 and includes the novel compounds discovered from 2018 to 2021.

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Kinases and kinase inhibitors

Cited by 3 publications

References 54 publications

Targeting the Plasmodium falciparum’s Thymidylate Monophosphate Kinase for the Identification of Novel Antimalarial Natural Compounds

Targeting the Plasmodium falciparum’s Thymidylate Monophosphate Kinase for the Identification of Novel Antimalarial Natural Compounds

A New Thienopyrimidinone Chemotype Shows Multistage Activity against Plasmodium falciparum, Including Artemisinin-Resistant Parasites

Bioactive Compounds from Marine Sponges: Fundamentals and Applications

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