Free Energy Perturbation (FEP): Another technique in the drug discovery toolbox
Introduction When I first started using CHARMM over 20 years ago as a PhD student, I regularly came across references ...
We’ve been working steadily over the last six months to improve on our offering to computational chemists and other power users. The result is Forge, a new application that combines all the features of FieldAlign and FieldTemplater into a single new package and adds a heap more of the functionality you’ve asked for. We are really pleased with the result and as we near release we thought we would let you in on the secrets that are coming soon.
The primary role of Forge is to help with decoding structure activity relationships and generating new molecule designs with meaningful activity predictions wherever possible. On the design side we’ve revamped the molecular editor to give you the flexibility to design molecules using fields in an interactive environment. Take a look at the screenshot below:
The screenshot shows the new drawing buttons on the left with ring templates which will please all those that asked for them and make drawing far less painful. There is a new button on the right “Align” will align the molecule that is present in the editor to the reference molecule giving you immediate feedback on a new design and giving you the ability to manually edit alignments. We call this “score while you draw”!
To enhance the understanding of structure activity relationships in your molecules we have introduced automated analysis of field patterns using a QSAR method and new alignment methods to give you more ligand centric views as opposed to the protein centric view that we have traditionally generated. The QSAR that we are introducing is a completely new 3D method that uses the field points around your ligands as sampling points for the field of a ligand. In effect we generate a irregular, non-lattice grid around the ligands which is then used to generate field samples on every molecule in the training set. Using PLS acrosss this dataset gives an indication of which regions of the field are contributing to the observed changes in activity but also generates a way of predicting activities for compounds of unknown activity. The QSAR model that you create can be exported to be used by others or used to help the design process including in the “score while you draw” feature. The QSAR is completely integrated into Forge with all the statistics that you would expect from a method of this type (see the screenshot below for an example). Of course 3D QSAR is not a panacea but in our hands this methods has greatly enhanced many of the customer projects that we have worked on.
Underlying these functionality improvements is a new version of our XED molecular mechanics force field that introduces some fundamental changes as well as field pattern improvements. The biggest change in the force field is the introduction of a completely analogue nitrogen atom type that can transition from planar to pyramidal depending on the degree of hydbridisation with surounding atoms.
Lastly, Forge is firmly a Cresset application and comes with the intuitive user interface that you have come to expect from us, plus a comprehensive wizard to guide you through the process of setting up experiments.