Which of my compounds is most likely to succeed?

Prioritizing compounds for synthesis using Torch

Prioritizing compounds for synthesis is a skilled scientific decision. Getting it right means targeting the right series to focus valuable lab time on the compounds most likely to succeed. The medicinal chemists’ challenge is to predict the likely effect of structural changes on biological activity. Torch is a desktop software tool that helps chemists answer the question, ‘Which of my compounds is most likely to succeed?’

Torch is an easy to use, scientifically robust desktop software tool that helps medicinal chemists design, optimize and prioritize molecules. It uses the 3D binding properties of molecules to compare and contrast new designs with existing knowledge, presenting the results together with key physico-chemical properties. Working with Torch, medicinal chemists can rapidly identify the best next molecule to synthesize.

Traditional drug design has put a great deal of emphasis on the 2D structure of compounds. However, small molecule drugs are recognized by and bind to proteins on the basis of their 3D electronic and shape properties. Cresset’s software uses reliable algorithms to calculate the field patterns of molecules to give a meaningful basis for the comparison of potential biological activity.

Bioisosteres have diffferent 2D structures but similar field patterns
Figure 1: The 2D structures (left) and field patterns (right) of cAMP (the natural substrate) and inhibitor of PDE3. The field patterns reveal that these two structurally diverse molecules are bioisosteres.

Using molecular fields, medicinal chemists gain insights into the biological activity of their molecules. They see how relatively simple changes can optimize the shape and electrostatic properties of their series. They gain understanding of the change in activity caused by electron donating or withdrawing substituents, and use this information to design the optimal solution. Comparing actives from multiple chemical series generates further design ideas and enables the transfer of SAR between series.

Torch is used by medicinal chemists on desktop PCs to guide lead optimization programs using a rational approach based around exploring and exploiting molecular field similarities. Torch uses a wizard style interface to set up experiments, guiding the user through each step of the process. The intuitive interface gives a high level of control over how molecules and alignments are displayed. Results are easily communicated to other members of the team as pictures, project files or using industry standard formats.

Torch can be used to assist medicinal chemists in their logical approach to designing and prioritizing novel scaffolds for series switching. Medicinal chemists at the James Black Foundation used Torch to design new chemotypes for cholecystokinin-2 (CCK2) receptor antagonists. They designed replacements for an undesirable dibenzobicyclo[2.2.2]octane (BCO) core. The newly designed indole and naphthyl derivatives were synthesized and found to possess a similar pKi to the early lead. The chemists used Torch to optimize their leads and to select the most promising candidates for synthesis.

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Figure 2: Aligned molecules can be viewed in Torch as a superimposed image or compared side by side. A range of presentation options allow structure, field points and surfaces to be turned on or off, and the display style and colors to be specified.

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