Projects

VirtualToxLab

VirtualToxLab™in silico predicition of the toxic potential of drugs and chemicals

The VirtualToxLab is an in silico tool for predicting the toxic potential (endocrine and metabolic disruption, some aspects of carcinogenicity and cardiotoxicity) of drugs, chemicals and natural products. It simulates and quantifies their interactions towards a series of proteins known to trigger adverse effects using automated, flexible docking combined with multi-dimensional QSAR (mQSAR). Currently, the VirtualToxLab comprises 16 models of proteins known or suspected to trigger adverse effects: the androgen, aryl hydrocarbon, estrogen α, estrogen β, glucocorticoid, hERG, liver X, mineralocorticoid, progesterone, thyroid α, thyroid β and peroxisome proliferator-activated receptor γ as well as the enzymes CYP450 1A2, 2C9, 2D6 and 3A4. Most important, the VirtualToxLab allows to rationalize a prediction at the molecular level by analyzing the binding mode of the tested compound towards all 16 target proteins in real-time 3D/4D. The distribution comprises a graphical-user interface (including a 3D/4D viewer and a 3D model builder). The VirtualToxLab runs in client–server mode and the interface supports Macintosh, Linux and Windows operating systems.

As of today, we have tested over 2,500 different compounds — drugs, chemicals, natural compounds — with respect to their affinity towards the 16 target proteins (AR, AhR, CYP1A2, CYP2C9, CYP2D6, CYP3A4, ERα, ERβ, GR, hERG, LXR, MR, PPARγ, PR, TRα, TRβ) and estimated their toxic potential. The results are shown here.

The VirtualToxLab contributes to two aspects of the 3R philosophy: First, it allows for an early recognition of potentially harmful substances, thus, replacing stressful animal tests in preclinical research and development as compounds with a significant activity towards any of the database surrogates are not cleared for further studies — including pharmacological and toxicological testing. Second, a widely used database of this kind would reduce the number of otherwise doubly-conducted (toxicity) tests at research laboratories focussed on identical or closely related biomedical targets.

Licenses

Three basic options of the VirtualToxLab are available: The OpenVirtualToxLab is free of charge and thought for Universities, governmental agencies, regulatory bodies, public hospitals and non-profit organizations with moderate need of the technology. Except for the rights to download the 3D coordinates of the ligand–protein complexes (PDB format), the OpenVirtualToxLab and the VirtualToxLab are identical. The VirtualToxLab is taylored for industrial customers and is available as client-server application (Premium) or on-site installation (Gold). Details are given below.

Option License Fee (Euros) Product
Open A: free
B: free
C: n/a
VTLBrowser, VTLViewer (3D/4D viewer), VTLBuilder (3D model builder); 800 tokens/year: full profile (16 target proteins) for 50 compounds or 800 individual tests (single-protein target) → More info
Premium A: 2,400.00 per year
B: 4,800.00 per year
C: 9,600.00 per year
VTLBrowser, VTLViewer (3D/4D viewer), VTLBuilder (3D model builder); 1,600 tokens: full profile (16 target proteins) for 100 compounds or 1,600 individual tests (single-protein target). 3D coordinates of all protein–ligand complexes (in PDB format). On-line support. Unused tokens are transferred to the next licensing period; additional tokens may be purchased at any time.
Gold A: n/a
B: n/a
C: on request
On-site installation with unlimited access to the technology. On-line and on-site support.
Trial A: 600.00
B: 1,200.00
C: 2,400.00
Three-month trial period including all tools (Interface, VTLBuilder, VTLViewer) and 400 tokens. Upon purchase of a VTL license, this amount will be credited in full. On-line support.
 A: Universities and Environmental NPO's; B: Governmental Agencies; C: Industrial Customers

Services

The VirtualToxLab services have been launched for institutional users with occasional need of the technology and without the manpower/background to analyze and interpret the data. Based on a structure drawing (e.g. ChemDraw), the Biographics Laboratory 3R performs all simulations and interprets the data. The customer is provided with a detailed report (cf. examples below).

Option Price (Euros/compound) Service
VTL A: 50.00
B: 100.00
C: 200.00
Full profile (16 target proteins), detailed report with data table(s), 3D image(s) and comments. → Example
VTL+ A: 100.00
B: 200.00
C: 400.00
Full profile (16 target proteins), detailed report with data table(s), 3D image(s) and comments. Analysis of the kinetic stability of the ligand–protein complex by means of a 2.0 ns molecular-dynamics simulation for the main target. Detailed energy profiles and VMD movie. → Example
VTL++ A: 125.00
B: 250.00
C: 500.00
Full profile (16 target proteins) employing double conformational sampling, detailed report with data table(s), 3D image(s) and comments. Analysis of the kinetic stability of the ligand–protein complex by means of a 5.0 ns molecular-dynamics simulation for the main target. Detailed energy profiles and VMD movie. In silico pharmacokinetic profiling of the ligand. → Example
 A: Universities and Environmental NPO's; B: Governmental Agencies; C: Industrial Customers

Documentation: → download (pdf, 21.6 MB)

References: Toxicol. Lett. 2015, 232, 519–532   → view/download
                  Toxicol. Appl. Pharmacol. 2012, 261, 142–153   → view abstract
                  ChemMedChem 2010, 5, 2088–2101   → view abstract
                  Mol. Inf. 2010, 1, 27–36   → view abstract
                  ATLA 2009, 37, 477–496   → view abstract
                  ALTEX 2009, 26, 183–193   → view abstract
                  Toxicol. Lett. 2009, 189, 219–224   → view abstract
                  ChemMedChem 2009, 4, 104–109   → view abstract
                  Toxicol. Lett. 2007, 173, 17–23   → view abstract
                  ChemMedChem 2007, 2, 78–87   → view abstract
                  ChemMedChem 2006, 1, 73–81   → view abstract
                  J. Med. Chem. 2005, 48, 5666–5674   → view abstract
                  J. Med. Chem. 2005, 48, 3700–3703   → view abstract
                  J. Med. Chem. 2002, 45, 2139–2149   → view abstract
                  J. Med. Chem. 2000, 43, 4416–4427   → view abstract
                  J. Am. Chem. Soc. 1998, 120, 4471–4477   → view abstract