Virtual Screening and Fragment Replacement to Find Novel Chemotypes for PDE4B Inhibitors

Starting with a known PDE4B inhibitor, Cresset ran a virtual screening experiment in Forge (formerly known as FieldTemplater) and a fragment replacement experiment in Spark (formerly known as FieldStere) to find new starting points for research. The results included known active compounds as well as several novel chemotypes.

Chronic obstructive pulmonary disease (COPD) is a common, progressive disorder of increasing prevalence in industrialized countries. COPD is an all-inclusive term that refers to a set of symptoms including chronic cough, expectoration, exertional dyspnea and a significant, progressive reduction in expiratory airflow that may or may not be partly reversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases. Several drugs have been marketed so far, and several molecular targets have been considered so far for therapeutic intervention.

This project explored the SAR of known PDE4B inhibitors extracted from Thomson Reuters’ Integrity database and used this to derive models that enabled scaffold hopping.

We first assumed that all molecules act at the same site on the same target. Using the 2D structures of the four chosen compounds shown in figure 1 as input, Cresset’s Forge calculated possible conformations for each compound, then used these to find a common field pattern across 200 representative conformations of each compound.

 
Figure 1: Four known PDE4B inhibitors, shown as 2D structures (left) and as 3D conformations with superimposed field patterns as calculated by Forge (right).Two separate experiments were then performed using the most active 654921 seed structure. Firstly a virtual screening experiment was carried out using Forge to identify bioisosteres from the Cresset databases of 4.5 million drug and drug-like compounds.

Secondly, Spark was used to find possible fragment replacements for a section of the 654921 molecule. Some of the results of these experiments are shown in figure 2, below:

 
Figure 2: The diverse structures that result from virtual screening in Forge (left) and fragment replacement in Spark (right) from the same seed structure. Each of these compounds are likely to show similar biological activity to the seed structure.These results include known active compounds as well as several novel chemotypes, which can then be taken forward as leads in the therapeutic prevention of COPD.

The project reported in this case study was originally presented as a joint poster between Thomson Reuters Scientific and Cresset at the EFMC Conference in Brussels in Sept 2010 Finch, C., Prous, J., Hoffmann, R., Buckley, G., Gardner, S., & Vinter, A.