Synthesis and characterization of potent inhibitors of Trypanosoma cruzi dihydrofolate reductase

Schormann, Norbert; Velu, Sadanandan E.; Murugesan, Srinivasan; Senkovich, Olga; Walker, Kiera; Chenna, Balachandra; Shinkre, Bidhan A.; Desai, Amar; Chattopadhyay, Debasish

doi:10.1016/j.bmc.2010.04.020

Cited by 38 publications

(33 citation statements)

References 26 publications

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“…However, the selectivity of this compound is very low [9]. Attempts to enhance the potency and selectivity of TMQ have achieved limited success until recently [27,28]. In contrast to TMQ, the SI of the analogue #66 against Sm DHFR over hDHFR reached 117.8, indicating its potential as a leading compound to develop an anti- S. mutans drug.…”

Section: Discussionmentioning

confidence: 99%

New small-molecule inhibitors of dihydrofolate reductase inhibit Streptococcus mutans

Zhang

Nguyen

McMichael

et al. 2015

International Journal of Antimicrobial Agents

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Streptococcus mutans is a major aetiological agent of dental caries. Formation of biofilms is a key virulence factor of S. mutans. Drugs that inhibit S. mutans biofilms may have therapeutic potential. Dihydrofolate reductase (DHFR) plays a critical role in regulating the metabolism of folate. DHFR inhibitors are thus potent drugs and have been explored as anticancer and antimicrobial agents. In this study, a library of analogues based on a DHFR inhibitor, trimetrexate (TMQ), an FDA-approved drug, was screened and three new analogues that selectively inhibited S. mutans were identified. The most potent inhibitor had a 50% inhibitory concentration (IC50) of 454.0 ± 10.2 nM for the biofilm and 8.7 ± 1.9 nM for DHFR of S. mutans. In contrast, the IC50 of this compound for human DHFR was ca. 1000 nM, a >100-fold decrease in its potency, demonstrating the high selectivity of the analogue. An analogue that exhibited the least potency for the S. mutans biofilm also had the lowest activity towards inhibiting S. mutans DHFR, further indicating that inhibition of biofilms is related to reduced DHFR activity. These data, along with docking of the potent analogue to the modelled DHFR structure, suggested that the TMQ analogues indeed selectively inhibited S. mutans through targeting DHFR. These potent and selective small molecules are thus promising lead compounds to develop new effective therapeutics to prevent and treat dental caries.

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Section: Discussionmentioning

confidence: 99%

New small-molecule inhibitors of dihydrofolate reductase inhibit Streptococcus mutans

Zhang

Nguyen

McMichael

et al. 2015

International Journal of Antimicrobial Agents

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“…The structure of DHFR-TS from Trypanosoma cruzi was first determined by Chattopadhyay in 2008 26 bound to NADPH and MTX (PDB ID: 3CL9) as well as NADPH and trimetrexate (PDB ID: 3CLB). Work in 2010 describes a series of diaminoquinazoline inhibitors that have IC 50 values between 27 and 57 nM for the T. cruzi enzyme 27 ; three structures of these complexes are reported (PDB ID: 3KJS, 3KJU, 3KJW). Additionally, Chitnumsub et al reported four structures of T. cruzi DHFR-TS bound to cycloguanil (PDB IDs: 3IRM, 3IRN), a dihydrotriazine derivative (C-448; PDB ID: 3INV), and a quinazoline derivative (Q-8) (PDB IDs: 3IRO) 28 .…”

Section: Crystal Structures Of Dhfr and Ts Published Between 2006–mentioning

confidence: 99%

Antifolate agents: a patent review (2006 – 2010)

Wright

Anderson

2011

Expert Opinion on Therapeutic Patents

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Introduction For over 50 years, drugs targeting the folate pathway have significantly impacted disease treatment as anticancer, antimicrobial and immunomodulatory agents. The discovery of novel antifolate agents with improved properties and superior activities remains an attractive strategy, both in academia and the pharmaceutical industry. Areas covered This review surveys the patent literature from 2006–2010 for small molecule inhibitors of enzymatic targets in the folate biosynthetic pathway. Expert opinion The pursuit of antifolates as anticancer and antimicrobial agents continues to be an active area of research. New patent disclosures reveal novel antifolate scaffolds, antifolates with improved drug-like properties and new strategies to effectively target cancer cells. The continued use of high resolution structural information has guided the discovery of several compounds. Owing to the need for high levels of potency and selectivity, especially in targeting pathogenic species, the use of high resolution crystal structures remains an important tool to guide the design of novel antifolates. Interestingly, the patents disclosing novel compounds were ones where X-ray crystallography was an integral component of the design process. Finally, a variety of new structures have been reported that may play an important role in the future development of therapeutic antifolates.

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“…In fact, Schormann et al . could design an inhibitor about 7 times more active (in terms of K i value) against TcDHFR than hDHFR by targeting the region close to Met49 (27). …”

Section: Resultsmentioning

confidence: 99%

TRAPP webserver: predicting protein binding site flexibility and detecting transient binding pockets

Stank

Kokh

Horn

et al. 2017

Nucleic Acids Research

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The TRAnsient Pockets in Proteins (TRAPP) webserver provides an automated workflow that allows users to explore the dynamics of a protein binding site and to detect pockets or sub-pockets that may transiently open due to protein internal motion. These transient or cryptic sub-pockets may be of interest in the design and optimization of small molecular inhibitors for a protein target of interest. The TRAPP workflow consists of the following three modules: (i) TRAPP structure— generation of an ensemble of structures using one or more of four possible molecular simulation methods; (ii) TRAPP analysis—superposition and clustering of the binding site conformations either in an ensemble of structures generated in step (i) or in PDB structures or trajectories uploaded by the user; and (iii) TRAPP pocket—detection, analysis, and visualization of the binding pocket dynamics and characteristics, such as volume, solvent-exposed area or properties of surrounding residues. A standard sequence conservation score per residue or a differential score per residue, for comparing on- and off-targets, can be calculated and displayed on the binding pocket for an uploaded multiple sequence alignment file, and known protein sequence annotations can be displayed simultaneously. The TRAPP webserver is freely available at http://trapp.h-its.org.

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Synthesis and characterization of potent inhibitors of Trypanosoma cruzi dihydrofolate reductase

Cited by 38 publications

References 26 publications

New small-molecule inhibitors of dihydrofolate reductase inhibit Streptococcus mutans

New small-molecule inhibitors of dihydrofolate reductase inhibit Streptococcus mutans

Antifolate agents: a patent review (2006 – 2010)

TRAPP webserver: predicting protein binding site flexibility and detecting transient binding pockets

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