|12 Nov 2014|
The Discovering Dengue Drugs research team has published a paper describing a new drug candidate that was discovered with the help of World Community Grid volunteers. This drug candidate has no known adverse risks, and seems to be an attractive candidate for preclinical studies. A new antiviral treatment would be hugely beneficial for the roughly half of the world’s population that is at risk of contracting dengue or other related viruses such as hepatitis C, yellow fever and West Nile.
"Identification of a Novel Inhibitor of Dengue Virus Protease through Use of a Virtual Screening Drug Discovery Web Portal"
Lay Person Abstract:
We report the discovery of a small molecule that inhibited the function of the dengue virus protease (NS2B-NS3pro). This molecule was discovered using the web portal DrugDiscovery@TACC, which we developed to facilitate access to supercomputer resources for structure-based virtual screening. This site extended drug discovery studies originally performed on IBM's World Community Grid and enabled drug-like commercially available small molecule libraries to be rapidly screened against several dengue virus protease structures. As proof-of-concept, we show that a small molecule identified using DrugDiscovery@TACC was a strong inhibitor of the dengue virus protease. In addition, this small molecule also inhibited the functioning of the protease of the related West Nile virus. This newly discovered dengue virus drug candidate has no chemical features associated with adverse toxicity, carcinogenicity, or mutagenicity risks and thus is attractive for additional preclinical drug studies.
We report the discovery of a novel small-molecule inhibitor of the dengue virus (DENV) protease (NS2B-NS3pro) using a newly constructed Web-based portal (DrugDiscovery@TACC) for structure-based virtual screening. Our drug discovery portal, an extension of virtual screening studies performed using IBM's World Community Grid, facilitated access to supercomputer resources managed by the Texas Advanced Computing Center (TACC) and enabled druglike commercially available small-molecule libraries to be rapidly screened against several high-resolution DENV NS2B-NS3pro crystallographic structures. Detailed analysis of virtual screening docking scores and hydrogen-bonding interactions between each docked ligand and the NS2B-NS3pro Ser135 side chain were used to select molecules for experimental validation. Compounds were ordered from established chemical companies, and compounds with established aqueous solubility were tested for their ability to inhibit DENV NS2B-NS3pro cleavage of a model substrate in kinetic studies. As a proof-of-concept, we validated a small-molecule dihydronaphthalenone hit as a single-digit-micromolar mixed noncompetitive inhibitor of the DENV protease. Since the dihydronaphthalenone was predicted to interact with NS2B-NS3pro residues that are largely conserved between DENV and the related West Nile virus (WNV), we tested this inhibitor against WNV NS2B-NS3pro and observed a similar mixed noncompetitive inhibition mechanism. However, the inhibition constants were ∼10-fold larger against the WNV protease relative to the DENV protease. This novel validated lead had no chemical features or pharmacophores associated with adverse toxicity, carcinogenicity, or mutagenicity risks and thus is attractive for additional characterization and optimization.
Access to Paper:
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