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Programs/Databases and
utilities
Oct 21, 2008 1) FAF-Drugs: ADME/tox Filtering: simple rules to remove some undesirable molecules 2) Compound Collection-Databases: small molecules in 3D with 3 levels of ADME/tox filtering and DiversitySet ChemBridge - Validation Set 3) Protein Electrostatics: electrostatic potentials and pKas 4) Python scripts, Awk, Unix, Shell: utilities to help managing some files 5) JME editor from P. Ertl (to draw and get SMILES) 6) JChemPaint vs 2.2.1 (to draw and get SMILES and draw from SMILES) 7) JMol (look at some molecules in 3D) 8) Similarity search for small molecules via eMolecules: SMILES input, search in several databases 9) Compute logP 10) AMMOS: refine compounds and docked molecules (get the software) 11) FAF-Drugs2: ADME/Tox (get the software) 12) MS-DOCK: accurate multiple conformation generator and rigid docking protocol for multi-step virtual ligand screening |
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1) ADME/tox prediction:
we have developed several filters, the code is written in Python
Abstract In silico screening based on the structures of the ligands or of the receptors has become an essential tool to facilitate the drug discovery process but compound collections are needed to carry out such in silico experiments. It has been recognized that absorption, distribution, metabolism, excretion and toxicity (ADME/tox) are key properties that need to be considered early on, even during the database preparation stage. FAF-Drugs is an online service based on Frowns (a chemoinformatics toolkit) that allows users to process their own compound collections via simple ADME/Tox filtering rules such as molecular weight, polar surface area, logP or number of rotatable bonds. SMILES (Simplified Molecular Input Line Entry System), CANSMILES (canonical smiles) or SDF (structure data file) files are required as input and molecules that pass or do not pass the filters are sent back in CANSMILES format. This service should thus help scientists engaging in drug discovery campaigns. Other utilities and several compound collections suitable for in silico screening are available at our site. FAF-Drugs can be accessed at http://bioserv.rpbs.jussieu.fr/FAFDrugs.html. The paper is published in Nucleic Acids Res. 2006, 34(Web Server issue):W738-44, by Miteva, Violas, Montes, Gomez, Tuffery and Villoutreix Title: FAF-Drugs: free ADME/tox filtering of compound collections (Go to PubMed) |
Go to FAF-Drugs |
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2) Compound
Collections-Databases
Montes and Villoutreix have generated several compound collections. These molecules from different Chemical vendors (Ambinter Asinex, ChemBridge, NCI, Specs) went through several ADME/tox filters and were transformed in 3D with Omega (OpenEye Scientific Software). Each molecule can have up to 50 structures. These collections are available at RPBS, they were put online by Dr. P. Tuffery. This project is done via a special agreement with OpenEye. Diversity set ChemBridge 2007 - Validation set |
collections are available at RPBS . .Check here |
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3) PCE: Electrostatic
computations for Proteins and pKa predictions
Dr. Miteva and Dr. Villoutreix have been working with the MEAD package (MEAD: Macroscopic Electrostatics with Atomic Detail, by Dr. D. Bashford). The program is now available online via a collaboration with Dr. P. Tuffery. Abstract PCE (protein continuum electrostatics) is an online service for protein electrostatic computations presently based on the MEAD (macroscopic electrostatics with atomic detail) package initially developed by D. Bashford [(2004) Front Biosci., 9, 1082-1099]. This computer method uses a macroscopic electrostatic model for the calculation of protein electrostatic properties, such as pK(a) values of titratable groups and electrostatic potentials. The MEAD package generates electrostatic energies via finite difference solution to the Poisson-Boltzmann equation. Users submit a PDB file and PCE returns potentials and pK(a) values as well as color (static or animated) figures displaying electrostatic potentials mapped on the molecular surface. This service is intended to facilitate electrostatics analyses of proteins and thereby broaden the accessibility to continuum electrostatics to the biological community. PCE can be accessed at http://bioserv.rpbs.jussieu.fr/PCE. The paper is published in Nucleic Acids Res. 2005, 33(Web Server issue):W372-5, by Miteva, Tuffery, Villoutreix Title: PCE: web tools to compute protein continuum electrostatics (Go to PubMed) |
Go to PCE |
| 4) Python Scripts to
process Surflex or FRED output and other utilities These scripts are written by D. Lagorce, they will be provided soon. For now: Script 1: extract molecules from a large .mol2 file |
(Get the script here) |
| 5) Java Molecular Editor
or JME Molecular Editor This Java program allows to draw, edit and display small molecules. You can draw a compound and generate the corresponding SMILES. JME has been written by Dr. Peter Ertl (Novartis). Message from Bruno: Thanks Peter for allowing non-commercial users to work with your package. WARNING THIS MAY NOT WORK WITH ALL BROWSERS. |
USE JME NOW |
| 6) JChemPaint This Java program was originally written by Christoph Steinbeck and is now developed by his group. This is a free editor for 2D chemical structures (Go here for more explanations) WARNING THIS MAY NOT WORK WITH ALL BROWSERS |
USE JChemPaint NOW |
| 7) JMol Jmol is a Java applet to view molecules in 3D This is a free viewer (Go here for more explanations) WARNING THIS MAY NOT WORK WITH ALL BROWSERS |
USE JMol to look at Butane
NOW USE JMol to look at a small Protein (this one is called Crambin) NOW |
| 8) eMolecules This is a chemical search engine, searching all the world's chemistry (more info here) |
Use eMolecules NOW |
| 9) Compute logP with jlogP [You can get information
about jlogP (here)] Lipophilicity
is the most often used physicochemical property in quantitative
structure-activity relationships (QSAR) studies because it is related
to the distribution of a bioactive substance between body fluids and
lipid-rich phases.
Its quantitative descriptor is the octanol-water
partition coefficient (POW; usually expressed as log POW), which is the
ratio of the solute concentration in the octanol to that in the aqueous
phase under equilibrium conditions at a given
temperature.
People also talk about logP
as the 1-octanol/water partition coefficient, please check some
articles about that.
If a molecule contains basic or acidic groups, it can be ionized and
its distribution in 1-octanol/water mixture becomes pH-dependent. The
pH-dependent distribution coefficient, logD, was
shown to correlate with a number of biological parameters, such as the
effective permeability in human jejunum, blood-brain barrier
permeability values and volume of distribution. If log P and pKa are known,
log D may be derived using the Henderson-Hasselbalch equation. Thus both coefficients are
important parameters for drug development. Hydrophobicity can be expressed as logP: this is the calucalted logarithm of the octanol/water partition coefficient of the molecule. The higher the logP, the more hydrophobic the molecule. Note that the logP values calculated by jlogP are very approximate. The important features and limitations of jlogP are listed below: -Allowed structures: Structures using C, N, H, O, P, S, and the halogens are allowed with the following limitations (jlogP will issue a warning if you attempt to calculate the properties of an 'illegal' structure): -Carbon atoms can make only 4 covalent bonds and cannot be charged. -Nitrogen atoms can make 3 or 4 covalent bonds (except in the case of NO2 where they can make 5 covalent bonds); nitrogens can be (+)-charged; (-)-charged N's are not allowed. -Oxygen atoms can make 1 or 2 covalent bonds; oxygens can be (-)-charged but not (+)-charged. -Sulfur atoms can make 2 covalent bonds (or 6 as in a SO2 group); they cannot be charged. -Phosphorus atoms can make 5 covalent bonds only (as in a PO4 group). logP calculation method: jlogP uses a modified version of the atom-additive methods used by Wang et al. (J. Chem. Inf. Comput. Sci. 1997, 37, 615-21 and Perspectives in Drug Discovery and Design 2000: 19, 47-66) in their xlogp software. Briefly, both programs categorize each atom in the molecule into one of 90+ types based on the element, its hybridization, and its neighbors. Each type has a characteristic contribution to the overall logP of the molecule. xlogP sums the individual atom contributions and applies 10 correction factors that take larger scale effects into account. jlogp 1.1 does not apply these correction factors at present. Charged groups: The only charged groups allowed by jlogP are N+ and O-. Because the logP of charged groups is highly dependent on pH, jlopP's logP estimates for charged molecules are very approximate. In General Biology, the key concepts that facilitate a basic understanding of structure-hydrophobicity relationships are: • Concept 1: Polar (-OH, -NH2, -C O, etc.) or charged (-O– or -N ) groups are hydrophilic. • Concept 2: Charged groups are more hydrophilic than uncharged groups. • Concept 3: Non-polar groups (-CH2-, -CH3, -SH, etc.) are hydrophobic. Most programs computing logP are not able to deal with charged structures, this is because the logP of a charged molecule is more complex to calculate and is highly dependent on pH. To compute logP of charged molecules, the Marvin package is among the best one. Yet, jlogP can also deal with charged structures according to the limitations described above. Overall, a computed logP of about -6 indicates that the molecule is very hydrophilic (for example, glycine ClogP = -3.9) while the ClogP of decane = 5.9. One small comment about logP from Brian White from the Biology Department, University of Massachusetts, Boston, Massachusetts. When trying to design a drug, one would like to measure its hydrophobicity by adding it to a flask containing water and octanol. Since water and octanol don’t mix well, you get two layers. If the drug is very hydrophilic, you will find it all in the water layer and none in the octanol. If the drug is very hydrophobic, you will find it all in the octanol layer and none in the water layer. If the drug is in between, you will find some in the water and some in the octanol. The ratio of the amount found in the octanol divided by the amount found in the water is called the octanol-water partition coefficient; this is abbreviated POW and is higher the more hydrophobic a molecule is. Since POW varies over a large range, it is convenient to take the base-10 logarithm of POW or log(POW). For example, if we consider a drug that is moderately hydrophobic. Suppose that if you put 10 grams of the drug into the octanol/water flask, shake it up, and let it come to equilibrium, you find 9.09 grams of the drug in the octanol and 0.909 grams of the drug in the water. The POW = 9.09/0.909 or 10 (10 times more of the drug goes into the octanol than the water). The log(POW) would be log(10) or 1. More information (with many examplex) about logP computations can be found for example in the ClogP user guide |
Use jlogP NOW |
| 10) AMMOS This is package to refine the 3D structures of compounds present in a file and a tool that allows energy minimization of pre-docked ligands in the context of the protein binding site. Pencheva T, Lagorce D, Pajeva I, Villoutreix BO, Miteva MA. BMC Bioinformatics. 2008 Oct 16;9(1):438. |
Get AMMOS NOW |
| 11) FAF-Drugs2 This is package for filtering a compound collection (ADME/Tox using many rules). Lagorce D, Sperandio O, Galons H, Miteva MA, Villoutreix BO. FAF-Drugs2: free ADME/tox filtering tool to assist drug discovery and chemical biology projects. BMC Bioinformatics. 2008 Sep 24;9(1):396 |
Get FAF-Drugs2 NOW |
| 12) MS-DOCK Sauton N, Lagorce D, Villoutreix BO, Miteva MA. MS-DOCK: accurate multiple conformation generator and rigid docking protocol for multi-step virtual ligand screening. BMC Bioinformatics. 2008 Apr 10;9:184. |
Get MS-DOCK |
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