ArticleJournal of computer-aided molecular design2011
Computer-assisted combinatorial design of bicyclic thymidine analogs as inhibitors of Mycobacterium tuberculosis thymidine monophosphate kinase.
Article in Journal of computer-aided molecular design, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 28 citations in OpenAlex.
- Structure-Guided Development of Mycobacterial Thymidine Monophosphate Kinase (MtbTMPK) Inhibitors: Unlocking New Frontiers in Tuberculosis Research.Current topics in medicinal chemistry · 2026Review
- In Silico Optimization of Inhibitors of the 3-Chymotrypsin-like Protease of SARS-CoV-2.Life (Basel, Switzerland) · 2025Article
- Improved Inhibitors Targeting the Thymidylate Kinase of Multidrug-ResistantLife (Basel, Switzerland) · 2025Article
- Structure-Based Design and Pharmacophore-Based Virtual Screening of Combinatorial Library of Triclosan Analogues Active against Enoyl-Acyl Carrier Protein Reductase ofInternational journal of molecular sciences · 2023Article
- Antiviral agents against COVID-19: structure-based design of specific peptidomimetic inhibitors of SARS-CoV-2 main protease.RSC advances · 2020Article
- Virtual design of novel Plasmodium falciparum cysteine protease falcipain-2 hybrid lactone-chalcone and isatin-chalcone inhibitors probing the S2 active site pocket.Journal of enzyme inhibition and medicinal chemistry · 2019Article
- How accurate is the description of ligand-protein interactions by a hybrid QM/MM approach?Journal of molecular modeling · 2017Article
- QSAR-driven design, synthesis and discovery of potent chalcone derivatives with antitubercular activity.European journal of medicinal chemistry · 2017Article
- Design of Thymidine Analogues Targeting Thymidilate Kinase of Mycobacterium tuberculosis.Tuberculosis research and treatment · 2013Article
- Structure guided development of novel thymidine mimetics targeting Pseudomonas aeruginosa thymidylate kinase: from hit to lead generation.Journal of medicinal chemistry · 2012Article
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Authors and funding
3 authors at 3 institutions in 4 countries.
Funding
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Abstract
Thymidine monophosphate kinase (TMPK(mt)) is an essential enzyme for nucleotide metabolism in Mycobacterium tuberculosis, and thus an attractive target for novel antituberculosis agents. In this work, we have explored the chemical space around the 2',3'-bicyclic thymidine nucleus by designing and in silico screening of a virtual focused library selected via structure based methods to identify more potent analogs endowed with favorable ADME-related properties. In all the library members we have exchanged the ribose ring of the template with a cyclopentane moiety that is less prone to enzymatic degradation. In addition, we have replaced the six-membered 2',3'-ring by a number of five-membered and six-membered heterocyclic rings containing alternative proton donor and acceptor groups, to exploit the interaction with the carboxylate groups of Asp9 and Asp163 as well as with several cationic residues present in the vicinity of the TMPK(mt) binding site. The three-dimensional structure of the TMPK(mt) complexed with 5-hydroxymethyl-dUMP, an analog of dTMP, was employed to develop a QSAR model, to parameterize a scoring function specific for the TMPK(mt) target and to select analogues which display the highest predicted binding to the target. As a result, we identified a small highly focused combinatorial subset of bicyclic thymidine analogues as virtual hits that are predicted to inhibit the mycobacterial TMPK in the submicromolar concentration range and to display favorable ADME-related properties.
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