Case studies and posters

Confidentiality is of fundamental importance to our clients. For this reason, our most impressive work is usually not publishable. We often carry out retrospective analyses of published projects in order to provide examples of our capabilities. Below you will find case studies on:

Structure-based design

Putting electrostatics and water at the heart of structure-based design (poster)

Protein interaction potentials and ligand fields, as implemented in Flare, are a powerful way of understanding the electrostatics of ligand-protein interactions. The inclusion of stable water molecules following a 3D-RISM analysis dramatically improves the precision of the method for the characterization of protein active sites.

Improving new molecule design using electrostatics (poster)

Exploring the application of ligand and protein electrostatics to the design of new molecules using our applications Torch and Flare.

Comparing ligand and protein electrostatics of Btk inhibitors

In this case study, protein interaction potentials implemented in Flare were used to calculate a detailed map of the electrostatic character of the protein active site of Bruton’s tyrosine kinase (Btk), and compared to ligands fields to get a detailed understanding of ligand binding and SAR.

Virtual screening

Adding pharmacophores to shape and electrostatics: Too much of a good thing? (poster)

Demonstrated that use of pharmacophore constraints with Cresset electrostatic and shape based scoring method is generally favorable.

Fragment hopping with Blaze

This case study uses different virtual screening methods to explore the performance of field and shape-based approaches on a fragment discovery project, comparing and contrasting the results from each.

Rapid and simple Blaze database population and searching using KNIME and Forge

In this case study, a Blaze database of approximately 200,000 compounds from ChEMBL2 was prepared in a seamless manner using a KNIME3 workflow and standard Blaze database creation routines.

A novel series of non-peptide small molecules for protein-protein interactions

Cresset’s consultants were asked to identify drug-like chemotypes to mimic the activity of a series of peptides. Several novel lead molecules were identified for the client, Senexis.

Virtual screening with 11-beta-HSD-1 resulting in diverse new leads

A client asked Cresset’s consulting team to generate new ideas for lead structures in this area, using the natural ligand as a starting point. Cresset’s scientists used Blaze to find new active structures with diverse chemotypes.

From 34-mer peptide to small molecule: Using fields to find new actives for a GPCR receptor from the natural peptide ligand

Cresset’s consultants were asked to identify novel active compounds for a class II GPCR receptor. There were no known small molecule inhibitors, so the only information available was the natural ligand, a 34 residue peptide. From sparse experimental data, four areas of the native ligand were identified as major binding regions. The field patterns of these regions were determined and used as input to a Blaze virtual screen. A 30% hit rate was achieved with the hits all being drug like small molecules.


Bioisosteric replacement

Rapid technique for new scaffold generation (poster)

We present the methodology together with applications to core replacement and to fragment growing/optimization.

Can you keep all the SAR in your head? Using biological contexts to find the critical SAR regions (poster)

This work presents a technique for locating activity cliffs in the context of the target active site. Using this method critical SAR regions are clearly and rapidly identified. Furthermore the reason for the activity differences between pairs of compounds is readily discernable, leading to a true understanding of the SAR landscape.

Using Cresset’s Spark to grow and link distant fragment hits with sensible chemistry (poster)

This poster demonstrates how applying Spark to fragments bound to the active site of UDG provided a range of interesting and synthetically-feasible suggestions that not only preserve the fragment geometry but also included important protein interactions in the linker.

Scaffold hopping into new DPP-IV protease inhibitors (poster)

We show how Spark can be used to rapidly generate potentially valuable chemical ideas for new DPP-IV inhibitors.

Rapid technique for new scaffold generation II: What is the best source of inspiration? (poster)

The creation of fragment databases from proprietary collections of compounds can be a powerful way of increasing the chemical diversity available to Spark.

Generating accessible, novel R-groups in hit-to-lead and lead optimization (poster)

Learn how combining the power of Spark with the use of ‘chemistry-aware’ reagent fragment databases allows for exploitation of specific chemistries in the laboratory.

What rings do medicinal chemists use, and why? (poster)

This poster examines what rings have been used by medicinal chemists and cluster them based on their substitution patterns and electrostatic properties.

Can I make this into a macrocycle? Effective methods for fragment growing, joining and cyclization (poster)

See how Spark successfully designs macrocycles that are identical or very similar to reported BRD4 macrocycle inhibitors.

Rapid and accessible in silico macrocycle design: Application to BRD4 (poster)

Macrocyclization of pharmaceutical compounds plays an increasing role in drug discovery. With restricted conformational flexibility, macrocycles can contribute to improved binding affinity, selectivity and drug-like properties. Prediction of effective macrocyclization strategies prior to synthesis is crucial. Spark, Cresset’s bioisostere replacement and scaffold hopping tool, allows for rapid and accessible macrocyclization design that retains the bioactive conformation and electrostatic character of a known active molecule.

Using Spark to design macrocycle BRD4 inhibitors

Macrocyclization of pharmaceutical compounds plays an increasing role in drug discovery. Macrocycles can provide several advantages such as favorable drug-like properties, and increased selectivity and binding affinity. Here we present a case study of designing macrocyclization strategies for reported BRD4 inhibitors with Spark, Cresset’s bioisostere replacement and scaffold hopping tool.

Using the Spark reagent databases to identify bioisosteric R-group replacements

In this case study, the reagent databases based on eMolecules building blocks available with Cresset’s Spark software for bioisosteric replacement were used to identify alternative R-groups for selective inhibitors of the c-Met Kinase. The results suggest that working in successive rounds of optimization, choosing for each Spark experiment the starter molecule with the best activity profile, is an excellent strategy to rapidly identify the R-groups associated with the highest activity or optimal overall profile. The use of databases derived from available reagents ensures that the results can be tethered to molecules that are readily synthetically accessible.

Displacing crystallographic water molecules with Spark

Spark was used to carry out a water displacement experiment, starting from the published X-ray crystal structure of a selective inhibitor of Bruton’s tyrosine kinase (Btk). Spark was able to displace the water molecule bridging the interaction between the inhibitor and the P-loop backbone residues of Btk, correctly identifying the same alternative bicyclic indazole fragments found in the original publication which makes a direct interaction with the protein. The availability of a sufficiently diverse source of reagents was crucial in demonstrating the feasibility of this approach.

Identifying bioisosteres of the benzazepine scaffold

Working from just a 2D fragment of a known active D3 antagonist we show how Spark was able to quickly identify a variety of alterantive scaffolds, some of which have proven D3 activity.

Providing new lead series and IP position and profile for delivering in-vivo activity

A three way collaboration between Cresset, the University of Newcastle and Sygnature Discovery.

Using Spark to Identify New Cores for PDE5 Inhibitors: Scaffold-Hopping Sildenafil

This case study details a Spark experiment to replace the heteroaromatic scaffold of Sildenafil. The excellent results demonstrate the superior performance of Cresset’s XED force field in describing aromaticity.

Using Spark Reagent Databases to Find the Next Move

Spark reagent databases are a great way to explore the chemistry that is accessible to you today. In this case study they are used to grow a fragment lead and generate novel and credible results.

Finding potential new IP with novel bioisosteres of mGluR5 modulators

This case study shows how Spark was used to find novel bioisosteres for mGluR5 modulators. The scaffold hopping technique using molecular fields identified existing and potential new intellectual property in this busy therapeutic space.


Visualization

A picture tells a thousand words: Summarizing SAR for medicinal chemists (poster)

See how Activity Atlas is a powerful way of summarizing SAR data in 3D. By combining information across multiple activity cliffs, it enables a global view of the critical points in the activity landscape.

Activity Atlas: A highly efficient method to extract key insights from SAR (poster)

Computational modeling techniques, including both structure and ligand centric methods, are still key for understanding SAR around positive and negative potentiators of ion channel currents.

Activity cliffs defining PI3K subtype selectivity identified, visualized and explained with Activity Miner (poster)

Presentation of a technique for locating activity cliffs in the context of the target active site. Using this method critical SAR regions are clearly and rapidly identified. Furthermore the reason for the activity differences between pairs of compounds is readily discernable, leading to a true understanding of the SAR landscape.

Selectivity profiles in Activity Atlas (poster)

Demonstrates how applying Activity Atlas to activity deltas rather than to absolute activities provides additional insight into the often conflicting requirements of selectivity across multiple subtypes.

Aromatic heterocycles modeled in TorchLite

The XED force field uses multi-poles to model negative electron density resulting in enhanced description of intramolecular interactions and substituent effects on aromatic systems. The effect of using the XED force field was studied by modeling the positive and negative molecular interaction fields around a series of well known heterocycles.

Correlating biological activity with field patterns for histamine H3 antagonists

This example shows the power of TorchLite to illuminate the relationship between field patterns and biological activity for histamine H3 antagonists.

Vancomycin modeled in TorchLite

The modeling of Vancomycin in TorchLite demonstrates the unusual nature of the electrostatic environment of this complex antibiotic.


Library design

Can you keep all the SAR in your head? Using biological contexts to find the critical SAR regions (poster)

This work presents a technique for locating activity cliffs in the context of the target active site. Using this method critical SAR regions are clearly and rapidly identified. Furthermore the reason for the activity differences between pairs of compounds is readily discernable, leading to a true understanding of the SAR landscape.

Using Cresset’s Spark to grow and link distant fragment hits with sensible chemistry (poster)

This poster demonstrates how applying Spark to fragments bound to the active site of UDG provided a range of interesting and synthetically-feasible suggestions that not only preserve the fragment geometry but also included important protein interactions in the linker.

Examining the diversity of large collections of building blocks in 3D (poster)

We demonstrate that it is computationally feasible to cluster very large data sets of compounds according to electrostatic and shape properties. The result is an extremely information-rich fragment library.

Generating accessible, novel R-groups in hit-to-lead and lead optimization (poster)

Learn how combining the power of Spark with the use of ‘chemistry-aware’ reagent fragment databases allows for exploitation of specific chemistries in the laboratory.

What rings do medicinal chemists use, and why? (poster)

This poster examines what rings have been used by medicinal chemists and cluster them based on their substitution patterns and electrostatic properties.

Can I make this into a macrocycle? Effective methods for fragment growing, joining and cyclization (poster)

See how Spark successfully designs macrocycles that are identical or very similar to reported BRD4 macrocycle inhibitors.

Rapid and accessible in silico macrocycle design: Application to BRD4 (poster)

Macrocyclization of pharmaceutical compounds plays an increasing role in drug discovery. With restricted conformational flexibility, macrocycles can contribute to improved binding affinity, selectivity and drug-like properties. Prediction of effective macrocyclization strategies prior to synthesis is crucial. Spark, Cresset’s bioisostere replacement and scaffold hopping tool, allows for rapid and accessible macrocyclization design that retains the bioactive conformation and electrostatic character of a known active molecule.

Using Spark to generate library design ideas

In this example, Spark is used to generate ideas for possible starting point for a library base on S-adenosyl methionine (SAM), a co-factor used as a biological methylation synthon.


SAR analysis

3D-QSAR: Why be square? (poster)

We present Forge, an integrated approach to producing 3D-QSAR models, utilizing our field point descriptors1. These descriptors are used first to align molecules, either using a free alignment or by first aligning common substructures. Once the molecules are aligned, the collective field points of the training set are used to derive a gauge-invariant set of sampling points, which reduces the number of descriptors that need to be considered while ensuring that all regions around the molecule which might contribute to activity are adequately sampled. Finally, sample values are calculated and a Partial Least Square (PLS) model built.

A picture tells a thousand words: Summarizing SAR for medicinal chemists (poster)

See how Activity Atlas is a powerful way of summarizing SAR data in 3D. By combining information across multiple activity cliffs, it enables a global view of the critical points in the activity landscape.

Activity Atlas: A highly efficient method to extract key insights from SAR (poster)

Computational modeling techniques, including both structure and ligand centric methods, are still key for understanding SAR around positive and negative potentiators of ion channel currents.

Activity cliffs defining PI3K subtype selectivity identified, visualized and explained with Activity Miner (poster)

Presentation of a technique for locating activity cliffs in the context of the target active site. Using this method critical SAR regions are clearly and rapidly identified. Furthermore the reason for the activity differences between pairs of compounds is readily discernable, leading to a true understanding of the SAR landscape.

Improving new molecule design using electrostatics (poster)

Exploring the application of ligand and protein electrostatics to the design of new molecules using our applications Torch and Flare.

Selectivity profiles in Activity Atlas (poster)

Demonstrates how applying Activity Atlas to activity deltas rather than to absolute activities provides additional insight into the often conflicting requirements of selectivity across multiple subtypes.

Deciphering Kinase SAR using electrostatics (poster)

Protein interaction potentials and ligand fields are a powerful way of understanding the electrostatics of ligand-protein interactions. The knowledge gained is invaluable for informing ligand design to optimize activity and selectivity.

Adding pharmacophores to shape and electrostatics: Too much of a good thing? (poster)

Demonstrates that use of pharmacophore constraints with Cresset electrostatic and shape based scoring method is generally favorable.

At the heart of medicinal chemistry design: The synergistic relationship between Forge and Spark

Forge’s Activity Atlas models are combined with Spark’s ability to suggest novel, synthetically accessible modifications for your lead structure to explore possible moves from a range of CDK2 inhibitors.

Activity Atlas analysis of sodium channel antagonists. Part I: SAR of the right-hand side phenyl ring

This case study demonstrates the use of Activity Atlas in analyzing the SAR of the phenyl ring in a small series of Nav1.7 sodium channel antagonists, in the absence of crystallographic information about the bioactive conformation.

Converting patent data into 3D maps of SAR

Activity Atlas was used to analyze the SAR of a large data set of Orexin 2 receptor ligands taken from the US patent literature, with the objective to quickly investigate and understand the electrostatic, hydrophobic and shape features underlying the receptor activity of a recently published scaffold.

Tackling selectivity with Activity Atlas

In this case study, Activity Atlas was used to analyze the SAR of a series of adenosine A1, adenosine A2a and adenosine A3 antagonists, with the objective to investigate and understand the electrostatic, hydrophobic and shape features underlying receptor selectivity.

A 3D-QSAR study on DPP-IV inhibitors

A robust 3D-QSAR (Quantitative Structure Activity Relationship) model was built for a data set of 73 dipeptidyl peptidase IV (DPP-4, a serine protease) inhibitors using Forge, Cresset’s powerful ligand-focused workbench for understanding SAR and design. Ad hoc Forge 3D display capabilities were used to visualize and interpret the model.

Deciphering complex SAR

Activity Miner was used to investigate the SAR for a series of DPP-IV inhibitors. Electrostatic differences around a key aromatic moiety accounted for the observed activity changes and were rationalized with respect to the protein structure.


Pharmacophore elucidation

Elucidating the bioactive conformation of CCR5 inhibitors

This case study shows how FieldTemplater, working from just a few 2D structures of known active CCR5 Chemokine Receptor inhibitors, was able of correctly reproduce the bioactive conformation of the CCR5 receptor inhibitor Maraviroc as derived from the 4MBS PDB crystal structure, without making use of the X-ray information about the binding mode of this ligand. Additionally FieldTemplater indicates the relative alignments and likely bioactive conformations of 3 further CCR5 inhibitors.

Activity Miner was used to investigate the SAR for a series of DPP-IV inhibitors. Electrostatic differences around a key aromatic moiety accounted for the observed activity changes and were rationalized with respect to the protein structure.


Docking

Docking Factor-Xa ligands with Lead Finder

In this case study, two different Lead Finder docking modes (standard and extra precision) were used in docking studies on a small number of Factor-Xa (FXa) protein-ligand complexes originally used in the CSAR 2014 benchmark exercise.