OpenEye has announced the release of OEDocking v3.0.1. This is a bug fix release to the FRED, HYBRID, and POSIT programs. Of note, the report generated by both FRED and HYBRID has been significantly improved with this release

CHANGES

• The program dockreport has been renamed to DOCKINGREPORT

NEW FEATURES AND IMPROVEMENTS

• The formatting of the DOCKING_REPORT has been significantly improved and now includes:
• Added a protein interaction fingerprint
• XLogP
• Polar Surface Area (PSA)
• Improved the geometry detection for hydrogen bond protein constraints in FRED and HYBRID. These constraints should now be tighter.

BUG FIXES

• Stereo isomer detection in POSIT was not handling bridgeheads properly, this caused some non-stereo molecules to be identified as such.
• Fixed a bug in FRED and HYBRID where clash detection between hydrogen bonding groups was occasionally too strict.

Optibrium have just announced that StarDrop 5.3 is now available, including many new features, the highlights include:

• Virtual Library Enumeration – The Nova plug-in module for StarDrop now has the added ability to quickly and easily enumerate a virtual library based on a template scaffold that you define with substitution points and variable fragments. You can sketch the groups to substitute at each point, select them from a user-defined or centrally administered library, or take them from a decomposition of another series using the R-group analysis tool in StarDrop
• Data visualisation - now allows you to apply interactive filters to your graphs and plots to quickly focus on the most interesting compounds. StarDrop now also supports the analysis of dates allowing you to explore variations of properties or scores with time
• Clustering - this new tool enables you to easily identify groups of similar compounds within a data set, based on either their structural similarity or properties
• Dataset Filtering - this helps you to remove compounds from a data set with unwanted sub-structures or property values. You can define any number of criteria with which to filter a data set
• Duplicate Removal - when combining compound data from multiple sources it’s common to end up with multiple copies of the same compound in a single data set. The duplicate removal tool makes it easy to find these and choose the entries that you want to keep.
• ADME QSAR – new model for predicting log([Brain]:[Blood]) (the old model remains available for consistency with previously calculated results)

The new SMARTCyp version 2.4 includes solvent accessible surface area (SASA) in the scoring function. SASA is computed using the 2DSASA algorithm from 2D coordinates.

  A paper describing the new models and their predictive accuracy on nine CYP isoforms is available in Molecular Pharmaceutics DOI

SMARTCyp 2.3 has been released with some additional improvements including: Improved energies for N-oxidations Empirical correction for unlikely N-oxidations of tertiary alkylamines A filtering functionality for excluding compounds with very low activation barriers to CYP-mediated oxidations A smiles string can now be input directly on the command line using the -smiles flag.   Available as usual at http://www.farma.ku.dk/smartcyp   The science behind the improved N-oxidations and the empirical correction has also been published in a paper in Angewandte Chemie: DOI  

Two brand new tools from COSMOlogic which might be of greater interest for all those working in drug design:

1) COSMOsim3D Based on an idea of Michael Thormann (Origenis) we have implemented COSMOsim3D as a very efficient method for alignment and 3D similarity using local sigma profiles, i.e. local histograms of the COSMO sigma surface on a 3D grid. By that molecules get aligned in a way that maximum similarity of the sigma surfaces is achieved. In a paper which has just got online in JCIM (see http://pubs.acs.org/doi/abs/10.1021/ci300205p) we demonstrate the extraordinary performance of this method for bioisoster search and drug activity class enrichment.

2) COSMOsar3D According to COSMO-RS theory, which is widely validated in fluid phase thermodynamics, the final grid of local sigma profiles produced at the end of a COSMOsim3D alignment of ligands should represent a complete set of descriptors for molecular interactions. Furthermore it can be shown that with these descriptors the free energy of binding of a ligand in a receptor should be a linear function of the descriptors, and thus be optimally suited for the PLS analysis usally applied in molecular field analysis. Therefore we implemented the COSMOsar3D method a new variant of the traditional comparative field analysis, know as CoMFA. And indeed, testing this idea on the Sutherland data set we could show that it outperforms the seven reported 3D-QSAR methods tested therein not only with respect to prediction accuracy, but also with respect to robustness with respect to grid position, grid size, and small misalignments of the ligands. (see http://pubs.acs.org/doi/abs/10.1021/ci30 0231t)

Everybody who likes to test these two methods on his datasets is invited to do this based on a free evaluation license. You can use the tools either stand alone, or integrated in the Open3DQSAR software (http://open3dqsar.sourceforge.net/)

I was at the Cresset Science Meeting last week and heard about the plans to update their comprehensive suit of drug discovery and design computational tools.

Together with an interesting updates to the tools the suite has undergone something of a makeover, all of the software tools have be renamed using a “Fire” theme and refocussed to specific users needs rather than the software capabilities. The renaming will not be complete until September so in the interim the links on some of the download pages still point to the originally named application.

TorchV10lite is a free 3D molecule viewing, editing and drawing application that shows your molecules in 3D overlaid with field patterns generated using their proprietary field technology together with 2D structure and physicochemical properties. It is the replacement of FieldView.

TorchV10 is a powerful design and 3D SAR tool for medicinal chemists. It is used to take leaps in structural design by identifying compounds with similar fields but different 2D chemical structures while maintaining or improving biological activity. It is the replacement for FieldAlign and due for release very soon.

SparkV10 is a powerful way of generating novel and diverse structures for your project.  sparkV10 uses Cresset’s field technology to find biologically equivalent replacements for key moieties in your molecule, enabling you to find new structures in new chemical space. You can then use calculated physiochemical properties to filter and select the best designs. sparkV10 is the exciting replacement for FieldStere and due for release very soon.

The three applications above look to be intended for use by Medicinal Chemists whilst the remaining two applications are perhaps better suited to those more experienced in computational chemistry.

ForgeV10 takes advantage of Cresset’s patented ligand comparison method to align, score and compare molecules from a biological viewpoint, using the shape and electrostatic character of your molecules to create qualitative and quantitative 3D models of activity. forgeV10 combines FieldAlign and FieldTemplater in a single application,

BlazeV10 uses the shape and electrostatic character of known ligands to rapidly search large chemical collections for molecules with similar shape and electrostatic properties. It is installed and runs on a Linux cluster but is operated through a web-browser, enabling access from any platform and multiple locations.

Many molecular visualisation/modelling tools seem to assume the charge associated with an atom sits as a point at the centre of the nucleus, whilst this makes the computation easy it does not really reflect what the electrostatic surface really “looks like”. Cresset has pioneered the use of field point descriptors to give a more accurate description of the charge around an atom and to enable better comparisons and visualisation. This has been shown to be particularly important when trying to understand some molecular interactions such as Aryl-Aryl interactions or creating bioisosteric replacements.

Cresset now have an impressive suite of tools for drug discovery and I hope to review them in due course.