A Review of Forge V10.2 on the cylindrical MacPro

Now that I have my new MacPro I thought it might be interesting to try out a couple of the software packages that I’ve previously reviewed. ForgeV10 allows the scientist to use Cresset’s proprietary electrostatic and physicochemical fields to align, score and compare diverse molecules. It allows the user to build field based pharmacophores to understand structure activity and then use the template to undertake a virtual screen to identify novel scaffolds. I’ve previously reviewed ForgeV10 and as it was formally known FieldAlign so I’m going to focus on the support for multiple processors and a few of the new features.

Multi-core Support

It is clear that we are not going to see major improvements in chip speed so to improve performance many scientific packages have taken advantage of the parallel processing capabilities of modern multicore chips. Indeed it could be argued that any scientific software developer not looking to exploit the modern chip architectures is not doing there users any favours.

This is the configuration of my new desktop machine.   Mac Pro  Z0P8 Configuration:

  • 3.5GHz 6-core with 12MB of L3 cache
  • 64GB (4 x 16GB) of 1866MHz DDR3 ECC
  • 512GB PCIe-based flash storage
  • Dual AMD FirePro D700 GPUs with 6GB of GDDR5 VRAM each

In the Forge preferences you can set the number of processors to use so I set it to 6 and then did a test run using a PDE4 test set. Rolipram is a known PDE4 inhibitor and there is an X-ray structure of the protein in the public domain 1RO6 I downloaded this structure and cleaned it up using MOE then saved Rolipram and the protein as mol2 files, I also had a file containing around 200 potential ligands as 2D structures in sdf file format. The test involved both conformation searching, minimisation and alignment in the protein. If you start with a file containing pre-computed conformations then you can omit first step. However in my experience the Cresset tools do a very good job at generating reasonable conformations, much better than many alternative tools.

Looking at Activity Monitor (above) we can see the 6 FieldEngine processes running at approx 100%, but it was clear that the CPU load was only around 50%. Talking to the excellent Cresset support it was clear that there was the opportunity to take advantage of hyper-threading

For each processor core that is physically present, the operating system addresses two virtual or logical cores, and shares the workload between them when possible. The main function of hyper-threading is to decrease the number of dependent instructions on the pipeline. It takes advantage of superscalar architecture (multiple instructions operating on separate data in parallel). They appear to the OS as two processors, thus the OS can schedule two processes at once. http://en.wikipedia.org/wiki/Hyper-threading.

So an an experiment I ran the same dataset but changed the number of cores used over the range 3-8 (8 is the maximum number of threads supported by Forge) in the Forge preferences. As you can see in the histogram below increasing the number of cores available reduces the time taken to process the structure file.

You can also access the falign module via the command line interface (CLI), and for this comparison I used 

Looking at Activity Monitor is was apparent that 12 FieldEngines were initiated.

I also tried using the -q option

The Command Line Interface

I have to say the help is probably the clearest and most comprehensive I have seen for a command line application!

From my results a back of the envelope calculation would suggest my machine would be capable of processing around 21,000 structures per day (100 conformations, 10 alignments) using the GUI to set up the calculation. Whilst the figures will vary depending on the protein and the small molecule structures this is a very impressive throughput. This would be ideal for looking at the hits from a high-throughput screen, or one could imagine using a docking program to rapidly evaluate a few million structures and then take the top 20-30 thousand structures and using Forge to provide an alternative evaluation. It could also be useful for evaluating all compounds from a ongoing MedChem project, or looking at the results from an off-target activity. Using the command line interface (CLI) it is possible to make use of more FieldEngines and to tune the calculation. For instance using -q option to reduce the number of conformations generated and faster alignments.

I should emphasise ForgeV10.2 is not a virtual screening tool, Cresset have another product Blaze that has been optimised for very high-throughput virtual screening. If you have ever looked at virtual screening results you will be aware of the strange conformations and unlikely interactions that can sometimes be found, ForgeV10.2 identifies high quality conformations and gives much more believable results, the improved quality does come at a computational cost but it certainly seems like the new MacPro is up to the task.

Other New Features

Version 10.2 brings the inclusion of Activity Miner that I’ve previously reviewed, Activity Miner from Cresset is a new tool designed to rapidly interrogate and decipher SAR in both Torch and Forge. Activity Miner is intended to help identify key elements of the SAR by starting from a set of aligned molecules and then automatically comparing them to each other. Each pair is given a ‘disparity’ value which reflects how much the activity changes relative to the structure.

There are also a number of bug fixes and minor tweaks including the addition of circular fingerprints (ECFP4) and circular pharmacophore fingerprints (FCFP6) as options for the 2D similarity method. Ligand Efficiency and Lipophillic Ligand Efficiency columns have been added to the Results table 

Last updated 7 May 2014

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