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 ...
‘Library design‘ is a phrase that can encompasses many approaches and workflows including the design of screening libraries or the design of lead optimization libraries. We offer computational chemistry software and services that can help you with many of these design processes. Here we detail an approach that we have used successfully for the design of ‘focussed screening libraries’. That is libraries aimed at improving the hit rates of high or medium throughput screening for specific biological entities or families or at difficult targets such as protein-protein interactions.
In our view the first step in designing something new is to thoroughly understand what has gone before. However, no one wants to spend weeks studying past history when we could be getting on with a design! Usually we take a pragmatic approach – understanding what has gone before is critical to success but must be accomplished in as short a time as possible. We always detail the time that we are going to spend on this stage and the impact that it is likely to have on the final design. Usually we can shortcut the process by working closely with our client; we can use their knowledge to fast track our own. Together we often both gain deeper insight than we achieve separately.
The second stage is the most critical for the outcome of the project – idea generation. We find that our ideas materialize as we review and understand the previous work, including relevant ligands or crystal structures of the biological targets. As our analysis approaches its conclusion we begin generating and refining our ideas on new chemical entities that could form the heart of a new design. Of course every project is different but one common theme is that the first set of compounds are rarely the best and the ideas have to be refined and improved. As this progresses we take careful consideration of the potential to decorate cores with different R groups, the capabilities and thoughts of the synthetic chemists that will create the final compounds and the project brief. Bringing all these different components together is critical to success.
Customers come to us to combine our approach with their own expertize. As an independent unit we are often asked to think ‘out of the box’ to create truly innovative products. This could be on well worked targets, orphan receptors or one of the more challenging projects which require more resources than can be accommodated internally.
We have extensive library design experience using different approaches.1, 2 Our custom designs have been used throughout our industry from large pharmaceutical companies to small biotechs with diverse hits being obtained in kinases, GPCRs and ion channels.
Our range of software products inspire and inform our customers to generate the best molecules that they can and we use the same applications on our projects. However, our service offerings benefit from early access to new science features in the main software products (such as Activity Miner) and from access to unreleased software and cutting edge science. For example the ability to study the electrostatic environment of a protein active site and relate proteins using this description.