ArticleACS chemical biology2009
Exploiting structural analysis, in silico screening, and serendipity to identify novel inhibitors of drug-resistant falciparum malaria.
Article in ACS chemical biology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 61 citations in OpenAlex.
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- Identification of Potential Druggable Targets and Structure-Based Virtual Screening for Drug-like Molecules against the Shrimp PathogenInternational journal of molecular sciences · 2023Article
- High-Order Epistasis in Catalytic Power of Dihydrofolate Reductase Gives Rise to a Rugged Fitness Landscape in the Presence of Trimethoprim Selection.Molecular biology and evolution · 2019Article
- A systematic and prospectively validated approach for identifying synergistic drug combinations against malaria.Malaria journal · 2018Article
- A Structural Basis for Biguanide Activity.Biochemistry · 2017Article
- An RNAi-based high-throughput screening assay to identify small molecule inhibitors of hepatitis B virus replication.The Journal of biological chemistry · 2017Article
- Understanding the molecular mechanism of substrate channeling and domain communication in protozoal bifunctional TS-DHFR.Protein engineering, design & selection : PEDS · 2017Review
- The Potential of Secondary Metabolites from Plants as Drugs or Leads against Protozoan Neglected Diseases-Part III: In-Silico Molecular Docking Investigations.Molecules (Basel, Switzerland) · 2016Review
- 3D-QSAR Studies on Barbituric Acid Derivatives as Urease Inhibitors and the Effect of Charges on the Quality of a Model.International journal of molecular sciences · 2016Article
- Identification of novel Interleukin-2 inhibitors through computational approaches.Molecular diversity · 2013Article
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- Winning the arms race by improving drug discovery against mutating targets.ACS chemical biology · 2012Review
- A chemical genomic analysis of decoquinate, a Plasmodium falciparum cytochrome b inhibitor.ACS chemical biology · 2011Article
- Antifolate agents: a patent review (2006 - 2010).Expert opinion on therapeutic patents · 2011Review
- Computer-aided molecular design of 1H-imidazole-2,4-diamine derivatives as potential inhibitors of Plasmodium falciparum DHFR enzyme.Journal of molecular modeling · 2011Article
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
Abstract
Plasmodium falciparum thymidylate synthase-dihydrofolate reductase (TS-DHFR) is an essential enzyme in folate biosynthesis and a major malarial drug target. This bifunctional enzyme thus presents different design approaches for developing novel inhibitors against drug-resistant mutants. We performed a high-throughput in silico screen of a database of diverse, drug-like molecules against a non-active-site pocket of TS-DHFR. The top compounds from this virtual screen were evaluated by in vitro enzymatic and cellular culture studies. Three compounds active to 20 microM IC(50)'s in both wildtype and antifolate-resistant P. falciparum parasites were identified; moreover, no inhibition of human DHFR enzyme was observed, indicating that the inhibitory effects appeared to be parasite-specific. Notably, all three compounds had a biguanide scaffold. However, relative free energy of binding calculations suggested that the compounds might preferentially interact with the active site over the screened non-active-site region. To resolve the two possible modes of binding, co-crystallization studies of the compounds complexed with TS-DHFR enzyme were performed. Surprisingly, the structural analysis revealed that these novel, biguanide compounds do indeed bind at the active site of DHFR and additionally revealed the molecular basis by which they overcome drug resistance. To our knowledge, these are the first co-crystal structures of novel, biguanide, non-WR99210 compounds that are active against folate-resistant malaria parasites in cell culture.
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Registered trials
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