Simple 3D Conformer Generation with Smi23D

Rich Apodaca — Wed, 12 Dec 2007 10:32:00 +0000

Three-dimensional conformer generation is a common problem in cheminformatics. The most convenient and generally-useful method for creating chemical structures is the 2D chemical structure editor; applications that require three-dimensional representations need a way to generate reasonable coordinates from 2D user input. Until recently, there were no options for doing so with Open Source software. This article shows how the Open Source package smi23d can be used to convert ordinary SMILES strings into three-dimensional molfile representations.

About smi23d

smi23d uses a two-stage process to generate 3D coordinates.; an initial pass with smi2sdf generates rough coordinates and subsequent refinement by mengine results in the final coordinates. The package was originally written in C by Kevin Gilbert and updated by Rajarshi Guha. As part of what appears to be a growing trend in cheminformatics, smi23d is licensed under the highly-permissive Apache License.

On a related note, the source code for a program called Frog is reportedly on its way into the Open Babel project.

Prerequisites

To build smi23d, you'll need to install Scons, a Make-like build utility written in Python. I was able to install the Scons rpm on my Linux system without a problem. smi23d uses no other dependencies.

Download smi23d

smi23d can be downloaded with Subversion:

$ svn co https://cicc-grid.svn.sourceforge.net/svnroot/cicc-grid/cicc-grid/smi23d/trunk smi23d

Building smi23d

With the source code in place, compilation is just a matter of running Scons:

$ cd smi23d
$ scons
...

Once the sources are compiled, we'll want to configure our system a bit:

$ cd build
$ ls
mmff94.prm  mmxconst.prm

$ cp ../src/smi2sdf/smi2sdf .
$ cp ../src/mengine/mengine .

The two files mmff94.prm and mmxconst.prm are parameter files needed by both smi2sdf and mengine.

With smi2sdf and mengine both in the build directory, we can create a simple test with the SMILES for Ivabradine:

$ vi test.smi
...

$ cat test.smi
CN(CCCN1CCC2=CC(=C(C=C2CC1=O)OC)OC)C[C@H]3CC4=CC(=C(C=C34)OC)OC

With everything ready to go, we can begin Stage one:

$ ./smi2sdf test.smi
Found 1 structures in test.smi
 field : MMX
 Atom Types: 169
 Bonds: 580 Bond3: 0 Bond4: 0 Bond5: 0
 Angle: 434 Angle3: 41 Angle4: 60 Angle5: 0
 Torsion: 697  Torsion4: 58 Torsion5: 0
 Vdw: 172 OOP: 91 Dipole: 474 Charge: 0 Improper: 0
 STBN: 26 ANGANG: 0 STRTOR: 0 VDWPR: 4


Input file  = test.smi
Output file = output.sdf
Param file  = mmxconst.prm
Log file    = error.log
Inorganic file = test_inorg.smi

Structure: 0 CN(CCCN1CCC2=CC(=C(C=C2CC1=O)OC)OC)C[C@H]3CC4=CC(=C(C=C34)OC)OC

You can view the result in an application like Jmol:

It's not much to look at, but we're not quite done yet.

Stage two is accomplished by using the output of Stage one as input to mengine:

$ ./mengine -o optimized.sdf output.sdf
 field : MMX
 Atom Types: 169
 Bonds: 580 Bond3: 0 Bond4: 0 Bond5: 0
 Angle: 434 Angle3: 41 Angle4: 60 Angle5: 0
 Torsion: 697  Torsion4: 58 Torsion5: 0
 Vdw: 172 OOP: 91 Dipole: 474 Charge: 0 Improper: 0
 STBN: 26 ANGANG: 0 STRTOR: 0 VDWPR: 4
 field : MMFF94
 Atom Types: 181
 Bonds: 448 Bond3: 0 Bond4: 0 Bond5: 0
 Angle: 1801 Angle3: 21 Angle4: 61 Angle5: 0
 Torsion: 674  Torsion4: 38 Torsion5: 95
 Vdw: 182 OOP: 112 Dipole: 0 Charge: 0 Improper: 0
 STBN: 286 ANGANG: 0 STRTOR: 0 VDWPR: 0

We now have a file called output.sdf. As you can see, it's a pretty good 3D representation of Ivabradine:

Conclusions

In this tutorial, we've seen how the Open Source program smi23d can be used to assign reasonable 3D coordinates to an arbitrary SMILES string. One very practical use of smi23d would be to process the output of 2D chemical structure editors prior to use in a 3D program. Future articles will discuss some of the possibilities.

Image Credit: Mary Mactavish

"Simple 3D Conformer Generation with Smi23D" by Geoffrey Hutchison

Sun, 16 Dec 2007 09:52:11 +0000

I don't know if this is the problem with mengine or not -- I didn't write the code.

In the current Open Babel engine, 2D files cause headaches. Some of the optimization parameters (particularly torsions) are undefined. So you get back NaN instead of a real coordinate.

I suspect mengine hasn't been rigorously tested on purely 2D files.

"Simple 3D Conformer Generation with Smi23D" by Rich Apodaca

Wed, 12 Dec 2007 20:31:14 +0000

Antony, yes, I noticed that.

It sounds like the problem is that you're using 2D coordinates with mengine. I tried the same thing and got either no output or strange output.

Still, being able to submit a 2D molfile and get a 3D molfile back would be very convenient.

"Simple 3D Conformer Generation with Smi23D" by ChemSpiderMan

Wed, 12 Dec 2007 18:46:00 +0000

Rich...we've been using smi23d on ChemSPider for a few weeks. http://www.chemspider.com/news/?p=79

It works...we use it in real time for every molecule so that it can be viewed in Jmol. I'd say our failure rates are about 10% of the time and this is explained over at the blog. We are feeding 2D SDFs rather than SMILEs and still need to fix it.

Depth-First: Simple 3D Conformer Generation with Smi23D