Practical experiences of using the 3D-QSAR tools in Forge, Application to RET Kinase Inhibitors

Practical experiences of using the 3D-QSAR tools in Forge, Application to RET Kinase Inhibitors was presented by Dr Bohdan Waszkowycz, Cancer Research at the Cresset European User Group Meeting 2015, Madingley Hall, UK.

The Cancer Research UK group at the Manchester Institute have been looking at ways to improve the selectivity of RET kinase inhibitors. They used the 3D-QSAR models in Forge and compared them with other 3D-QSAR methods. They concluded that building a successful and robust QSAR model takes time and patience, but Forge offers a user-friendly approach to building 3D-QSAR models.

In recent years RET kinase has been implicated in lung cancer and thyroid cancer, so there is a large potential market for a compound that can inhibit it effectively. There are a few known inhibitors used in the clinic, but they have not been designed specifically for the target but hit a range of kinases,

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Field based analysis of kinome ligand space

Dr Marcin Krol, Selvita, presented ‘Field based analysis of kinome ligand space’ at the Cresset European User Group Meeting 2015. He demonstrated how a Cresset field based analysis of kinome ligand space let them identify the chemical features responsible for the activity profile of kinase inhibitors.

Consensus field points across a cluster explained the observed structural features of kinase-inhibitor interactions. The field alignment of compounds could be successfully used to identify the chemical features for a particular activity profile.

Selvita has a small computational chemistry group that supports the work of the medicinal chemists.

Kinases are a family of enzymes that regulate the majority of cellular signalling pathways, including cell growth, differentiation, proliferation, angiogenesis, apoptosis, cytoskeletal rearrangement, metabolism. The deregulation of kinases leads to many diseases. The human kinome contains 518 protein kinases. There are about 30,000 kinase inhibitors available in the public domain ChEMBL with biochemical data.

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Spatial overlap of peptide hotspots and canonical drug pockets in a model enzyme

Spatial overlap of peptide hotspots and canonical drug pockets in a model enzyme was presented by Dr Walraj Gosal, Senior Scientist, Isogenica at the Cresset European User Group Meeting 2015.

Walraj’s talk described the process of moving from peptides from molecular display to small molecule inhibitors, with the help of Cresset technology. In collaboration with Cresset and Biolauncher, the team found that Cresset’s field patterns based on peptides can be used to find new inhibitors. The work was funded by the TSB (Technology Strategy Board).

Molecular (CIS) display1 is an Isogenica technology that allows you to find novel peptides and protein scaffolds that bind a given target.

Walraj described the basic problem: we don’t know how to move from the primary sequence to the precise 3D fold of the protein. He described it as the ultimate needle in a haystack problem,

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Optimization of protein kinase inhibitors – how structural information can help

At the Cresset European User Group Meeting 2015, Dr Daniel Kuhn presented a case study of the optimization of a c-Met protein protein kinase inhibitor from a high-throughput screening (HTS) hit through to a clinical compound. He focused on how structural information can inform the drug design process and also included retrospective Spark analysis that showed its effectiveness at identifying promising bioisosteres.

When taking a hit through to a lead, there are multiple parameters that need to be optimized, including potency, off-target activity, kinase selectivity, and the intellectual property freedom to operate. In all of these cases, structural information can help to guide you in the right direction.

c-Met is an established cancer target. The HCF/c-Met pathway is frequently deregulated in human cancer, and the overexpression of c-Met and or HGF correlates with aggressive tumor behaviour and poor clinical prognosis.

The starting point for the work was an HTS screen for novel c-Met inhibitors,

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Should I sow QM in my fields?

Should I sow QM in my fields? was presented by Dr Ewa Chudyk, Senior Scientist, Evotec at the Cresset European User Group Meeting 2015.

Ewa compared Cresset’s molecular mechanics force field with some more computationally intensive QM approaches. Her work showed that both the QM and the MM approaches were proven to be complementary and useful in inhibitor optimization. She also concluded that the QSAR approach in Forge was equally as good as the QM method.

Evotec are a contract research organization. Ewa set out to assess how useful Cresset’s tools can be for Evotec’s drug design projects. Her group was interested in comparing Cresset approaches with QM approaches. Inspired by Cresset fields, she also investigated fields around the proteins and whether it is possible to observe complementarity between fields around proteins and ligands.

When trying to describe molecular systems simpler,

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