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.

 PDE4 Structures and Template
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:

 PDE4 results
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.

September Design a Molecule

Detailed steps on how to enter the design competiton are presented below. Or watch the video version.

  1. Enter the competition to get everything you need
  2. Download the zip file using the link in the email that you get sent
  3. Unzip the downloaded file and follow the instructions in the readme document
  4. Install FieldAlign and FieldView from the “Software” folder
  5. In the “Competition” folder Double click the left mouse button on the FieldAlign project: “START_HERE_Sep11.fpj” to open this file in FieldAlign.
  6. Note two 2d molecules present in the molecule table: the reference (yellow block background) and four disconnected fragments (query)
  7. Select the query molecule in the table with the left mouse button (should turn to a blue background).
  8. Right click and select “Edit a copy of the selected molecule” to open the Molecule editor.
  9. Hold LMB on background and move mouse to rotate view.
  10. Edit (add atom) by dragging and holding LMB from a fragment. Ctrl-Z will undo. Hold Ctrl will toggle selection mode. Delete will delete selected atoms.
  11. Repeat to connect the fragments and design the replacement core using whichever atoms you wish: Select from the left hand atom menu; double click on a bond to toggle bonding.
  12. Minimise core only: Using the selection tool highlight the core (cyan) click minimise.
  13. Once you are happy: Save to exit the editor.
  14. To align the new molecule query and calculate a similarlty score: Click process (calculate icon) in the top menu.
  15. Repeat the process to refine the design or start again from the fragments.
  16. Once you have a winning design, export the molecule: Select the molecule to export by left clicking on it in the table then use File menu -> Export -> Export selected molecule
  17. Save the molecule to an sdf file
  18. Upload the molecule to enter or send it to

Video tips for September Design a Molecule

Drug Repositioning – IMPDH

Inositol monophosphate dehydrogenases (IMPDH) are vital enzymes in the production of GMP, GDP and GTP. IMPDH is important for cell growth and its inhibition is potentially useful in immunosuppression, anticancer therapy, psoriasis, rheumatoid arthritis and antiviral chemotherapy.

Our client, a small biotechnology company, wished to find new candidates for IMPDH from existing drugs that had been developed for other indications. Such compounds are more likely to be well tolerated and easily deliverable with good ADME and toxicity profiles, and were therefore lower risk candidates.

Six known human IMPDH inhibitors (four of which are shown below) were used to Field search the World Drug Index (WDI). The putative bioactive conformations of each ligand were derived using FieldTemplater to compare the six known ligands with ligands from available X-ray structures. 14 seed structures, covering all the putative bioconformers were then screened against the whole database using FieldScreen. The top 1,000 results from each search were then analysed to find the drugs that were common to as many of the seeds as possible.

4 IMPDH actives used as seeds

19 drugs were found that were common to 10 or more of the seeds. 13 of these are shown below:

13 result molecules

It is striking that these drugs are associated with therapeutic actions that could be related to the known action of IMPDH (with the possible exception of the relaxants). Detailed investigation of a related series of IMPDH inhibitors has revealed that the oxazole moiety can act as a potential source of reactive meta
bolites, which can cause toxic side-effects (Beevers 2006). Significant resource has been employed to replace this undesirable moiety by various groups. It is notable that none of the drugs identified by Cresset contains this moiety. Further investigation of this list has not been possible but one literature reference has been found that associates omeprazole and other HK-ATPase inhibitors with immunomodulation (Peddicor 1999).


Beevers et al. Bioorganic & Medicinal Chemistry Letters 16 (2006) 2535-2538

Peddicor T. E., Olsen K. M., Collier D. S. (1999) Crit. Care. Med. 27 (1): 90-4


Download this article in PDF format here.

New Directions in Statins Research

Atorvastatin was the world’s best selling drug in 2006 with global revenues of over $13B. Key patents in the area protect 5-membered heterocycles at the core of the structure. Cresset reinvestigated the core of Atorvastatin using FieldStere, looking for novel, chemically tractable molecules to serve as potential alternative HMG-CoA reductase inhibitors.

Atorvastatin showing region chosen to be replac ed

The 2D structure of Atorvastatin was pasted into FieldStere and the central core was selected for replacement (blue, below). It was felt that the carbonyl group of the core of Atorvastatin formed a key interaction with the protein and hence a ‘Field constraint’ was added to the FieldStere query such that this interaction was required to be present in bioisosteric replacements. Similarly, the iso-propyl group is known to be important for maintaining activity at HMG-CoA reductase and hence a constraint was added such that bioisosteres that lacked hydrophobicity in this region would be down weighted.

FieldStere searched 600,000 moieties for bioisosteric replacements of the core group that contained an aromatic ring. The resulting hit list was filtered within FieldStere to remove results with similar structures to Atorvastatin and those with high calculated logP. A first pass visual inspection of the top scoring results led to the selection of 7 bioisosteres for further investigation (below left).

Atorvastatin and bioisostere aligned

A second round of selection using FieldStere’s 3D superposition of the final molecules on the Atorvastatin target structure (shown for one example above right) combined with physicochemical properties gave 3 series that were not covered by Pfizer’s core patent protection. These were selected for further evaluation (below).

Atorvastatin bioisosteres

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