ArticleJournal of computer-aided molecular design2011
Structure-guided fragment-based in silico drug design of dengue protease inhibitors.
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 15 papers.
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Who cites it
15 citing papers in PubMed, 56 citations in OpenAlex.
- Achievements and Approaches in the Search for Small-Molecule Dengue NS2B/NS3 Inhibitors.Current medicinal chemistry · 2026Review
- Design, combinatorial synthesis and cytotoxic activity of 2-substituted furo[2,3-d]pyrimidinone and pyrrolo[2,3-d]pyrimidinone library.Molecular diversity · 2023Article
- Phytochemical Compound Screening to Identify Novel Small Molecules against Dengue Virus: A Docking and Dynamics Study.Molecules (Basel, Switzerland) · 2022Article
- A short survey of dengue protease inhibitor development in the past 6 years (2015-2020) with an emphasis on similarities between DENV and SARS-CoV-2 proteases.Bioorganic & medicinal chemistry · 2021Review
- Targeting the protease of West Nile virus.RSC medicinal chemistry · 2021Review
- Fragment-based screening with natural products for novel anti-parasitic disease drug discovery.Expert opinion on drug discovery · 2019Review
- Strategies Towards Protease Inhibitors for Emerging Flaviviruses.Advances in experimental medicine and biology · 2018Review
- Molecular docking NS4B of DENV 1-4 with known bioactive phyto-chemicals.Bioinformation · 2016Article
- In vitro evaluation of novel inhibitors against the NS2B-NS3 protease of dengue fever virus type 4.Molecules (Basel, Switzerland) · 2013Article
- The flavivirus protease as a target for drug discovery.Virologica Sinica · 2013Review
- New binding site conformations of the dengue virus NS3 protease accessed by molecular dynamics simulation.PloS one · 2013Article
- Current progress in Structure-Based Rational Drug Design marks a new mindset in drug discovery.Computational and structural biotechnology journal · 2013Review
- Ligand pose and orientational sampling in molecular docking.PloS one · 2013Article
- Drug design for ever, from hype to hope.Journal of computer-aided molecular design · 2012Article
- Ligand-bound structures of the dengue virus protease reveal the active conformation.Journal of virology · 2012Article
Corrections and comments
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Authors and funding
9 authors at 6 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
An in silico fragment-based drug design approach was devised and applied towards the identification of small molecule inhibitors of the dengue virus (DENV) NS2B-NS3 protease. Currently, no DENV protease co-crystal structure with bound inhibitor and fully formed substrate binding site is available. Therefore a homology model of DENV NS2B-NS3 protease was generated employing a multiple template spatial restraints method and used for structure-based design. A library of molecular fragments was derived from the ZINC screening database with help of the retrosynthetic combinatorial analysis procedure (RECAP). 150,000 molecular fragments were docked to the DENV protease homology model and the docking poses were rescored using a target-specific scoring function. High scoring fragments were assembled to small molecule candidates by an implicit linking cascade. The cascade included substructure searching and structural filters focusing on interactions with the S1 and S2 pockets of the protease. The chemical space adjacent to the promising candidates was further explored by neighborhood searching. A total of 23 compounds were tested experimentally and two compounds were discovered to inhibit dengue protease (IC(50) = 7.7 μM and 37.9 μM, respectively) and the related West Nile virus protease (IC(50) = 6.3 μM and 39.0 μM, respectively). This study demonstrates the successful application of a structure-guided fragment-based in silico drug design approach for dengue protease inhibitors providing straightforward hit generation using a combination of homology modeling, fragment docking, chemical similarity and structural filters.
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