Frog v2.14
FRee On line druG conformation generation.

What is Frog2 ?

Frog2 is a major evolution of Frog v1.01. It improves several issues of Frog1 (among which ring hydrogen management during conformational sampling, on the fly ring conformation generation, better diversity in conformational sampling, ...).

Frog2 features:
Frog (Nucleic Acids Res. 2007 35:W568-72) is based on Frowns (, a chemoinformatics toolkit written in python, to which several features have been added.
Frog2 (Nucleic Acids Res. 2010 38:W622-7) also embedds DG-AMMOS and AMMOS ( features for ring generation and energy minimization.
Frog2 still has some limitations (as almost every other package of the field).

Launch Frog2
More information

c1(nn(c(c1Br)C)CC(Nc1ncccc1C1CCC[NH+]1C)=O)[NH](O)=O ==> #1: c1(nn(c(c1Br)C)CC(Nc1ncccc1[C@H]1CCC[N@H+]1C)=O)[NH](O)=O
#2: c1(nn(c(c1Br)C)CC(Nc1ncccc1[C@H]1CCC[N@@H+]1C)=O)[NH](O)=O
#3: c1(nn(c(c1Br)C)CC(Nc1ncccc1[C@@H]1CCC[N@H+]1C)=O)[NH](O)=O
#4: c1(nn(c(c1Br)C)CC(Nc1ncccc1[C@@H]1CCC[N@@H+]1C)=O)[NH](O)=O

1: isomer1
2: isomer2 3: isomer3 4: isomer4

1. History
2. Features
3. Limitations
4. Usage
5. Time considerations
6. Examples, sample tests
7. Concepts
8. Validation
9. Availability (news since 2009 January)
10. Citations

1: Weininger, D. SMILES, a Chemical Language and Information System. 1. Introduction to Methodology and Encoding Rules. J. Chem. Inf. Comput. Sci. 1988, 28, 31-36
2: Arthur Dalby et al., J. Chem. Inf. Comput. Sci, 1992, 32, 244-255
3: Tripos Mol2 File Format
4: Lagorce D, Pencheva T, Villoutreix BO, Miteva MA. DG-AMMOS: a new tool to generate 3d conformation of small molecules using distance geometry and automated molecular mechanics optimization for in silico screening. BMC Chem Biol., 2009, 9, 6.
5: Pencheva T, Lagorce D, Pajeva I, Villoutreix BO, Miteva MA. AMMOS: Automated Molecular Mechanics Optimization tool for in silico Screening. BMC Bioinformatics. 2008, 9, 438.


6: Halgren T. A.; Merck Molecular Force Field: I. Basis, Form, Scope, Parameterization, and Performance of MMFF94 (490-519), II. MMFF94 van des Waals and Electrostatic Parameters for Intermolecular Interactions (520-552), III. Molecular Geometries and Vibrational Frequencies for MMFF94 (553-586), IV. Conformational Energies and Geometries for MMFF94 (587-615), V. Extension of MMFF94 Using Experimental Data, Additional Computational Data, and Empirical Rules (616-641). J. Comp. Chem., 1996, Vol.17, Nos. 5 & 6

Note: Please check the Input types and format before running  a job.  Most erroneous results come from improper specification of the input. Double check smiles with regards to aromaticity, and carboxyl groups. E.g. see the difference between: C(=C(CC(=O)O)\C(=O)O)/C(=O)O and C(=C(CC(O)O)\C(O)O)/C(O)O
For scratch generation, prefer not specifying the hydrogens in the input.
Note on conformations / processing:
Using "Quick3D" or "Single", the first conformation not presenting strong steric clashes will be returned.This is intended to provide rapidly a correct 3D geometry of the compound
for one or all its isomers.
Only using "Multi", conformations of low energy are returned. Be aware that this is under current optimisation on two directions: (i) relevance of the lowest energy
conformations (ii) computational speed. At present too large compounds still require important computational time. This is under investigation.

Note on formats:
  1. Smiles files should be on the form of one smiles per line, such as:
O=C(CCCCCCCCCC[C@H]1[C@@H]2[C@@H](c3c(C1)cc(cc3)O)CC[C@@]1([C@@H](CC[C@@H]21)O)C)[N@@](C)CCCC compound_Identifier
O=C(CCCCCCCCCC[C@H]1[C@@H]2[C@@H](c3c(C1)cc(cc3)O)CC[C@@]1([C@@H](CC[C@@H]21)O)C)[N@](C)CCCC  another_compound_identifier
O=C1[C@@H]2[C@H](N[C@H](N1)N)[N@](CCC(CO)CO)[CH]N2 TKinh5_penciclovir_1KI3pdb

  1. The mol2 format is described here.
  1. The sdf format should be on the form (Note the $$$$ line):
sdf description

Time considerations:
Frog2 engine is, in our assessment, much faster than Frog1'. On the astex test set (83 compounds) Frog2 (off-server) required 11 minutes.
Using comparable parameters, Frog1 generated the same collection in 103 minutes. The server calculation times are however usually slower than this, since several additional
operations such as image generation are performed, and since the calculations are performed on a cluster on which the cpu load is variable.


  1. Smiles input disambiguation
Paste smiles: 
Select Unambiguate.
Resulting smiles are:



A more complex sample test (19 smiles) can be accessed here.
The unambiguation results (38 smiles) can be accessed here.

  1. 3D generation from scratch
The results of the single generation (33 compounds) can be accessed here. (mol2 format) (the difference between 38 and 33 stands for axial/equatorial conformations possible for some cycles, and the fact that Frog randomly selected a maximum of 8 isomers upon 16 for 1 compound).
The results of the multi generation (10 conformations at max per isomer) can be accessed here. (mol2 format, 275 conformations) (note: for some compounds, less than 10 conformations of low energy were identified).

Some 3D conformations generated using Frog2.0b (multiconformations) - starting from these smiles representation, asking for no disambiguation, energy window of 25 kCal/mole, 50 conformers - , for 103 compounds of the astex collection for which experimental data is available here can be accessed here (2637 conformers).
  1. 3D generation from 3D input
Here is an example of input of ten compounds of the astex test set. Ran asking for 50 conformations per compound, the results are here.

  1. Examples of conformational sampling

Left: experimental conformation
Right: diversity of 50 conformations generated
using Frog2, from scratch
(removing 3D information prior to 3D generation)
HIV1 Frog-HIV1

Left: experimental conformation.
Right: diversity of 50 conformations generated
using Frog2, from scratch.

Older tests:

Random test upon 992 compounds from Specs, Chembridge and Ambinter, using as values of energetic treshold of 100.0, number of Monte Carlo steps of 100, number of conformations of 10.
The input smiles are here.
The unambiguated smiles (1238) are here.
The mol2 output (12668 conformers) is here.
The log file is here.
Compounds not processed (might not be ADME/Tox compliant) here.
Note: the number of 12668 (i.e. more than 1238 x 10) is due to componds for which axial equatorial conformers have been considered. See for instance compound Chembridge-6439335, 2 smiles to describe the isomers, but 4 conformers considered due to axial/equatorial conformations.


7: Sadowski, J.; Gasteiger, J. From Atoms and Bonds to Three-Dimensional Atomic Coordinates: Automatic Model Builders. Chem. Rev. 1993, 93, 2567-2581

compound.png ==>
Compound decomposition as cycles, linkers, appendices.

Validation tests:
November 2009: A run of Frog2 over 10,000 compounds of the Chembridge diverset using disambiguation resulted in the generation of conformers for 9829 compounds (Frog failed for less than 2% (171) compounds). The total numer of conformers generated was of 525583. Execution time was of 160mn.


Using Frog, please cite: