Computational approaches to ion channel drug discovery

In October, I presented Computational approaches to ion channel drug discovery at the ‘USA Integrated Drug Discovery Spotlight Event: Overcoming Challenges in Ion Channel Drug Discovery and Safety’ hosted by Concept Life Sciences and Metrion Biosciences.


Structure-based molecular modeling approaches are probably the most acceptable form of computationally driven rational design deemed useful by the medicinal chemistry community for drug discovery. For unliganded projects, invariably, medicinal chemistry is a painstakingly slow process.

Ion channels are inherently difficult protein targets to tackle as very few have been crystalized. Strangely, it seems that the greater the knowledge we accumulate – the deeper the complexity.

Alternative approaches e.g., chemogenomics and good ligand centric approaches, are vital to squeeze out all valuable insights from this ‘costly’ SAR data.

Cresset has a reputation for producing powerful software for ligand-centric molecular modeling. Analyses involving molecular 3D shape and accurate electrostatics, via Cresset’s proprietary multipole force field (XED), allow fast and informative interrogation of SAR in the absence of structure data.

I describe the current diversity of the ion channel target space and highlight some of the issues faced. Flare expands Cresset’s product portfolio into structure-based molecular design, bringing our electrostatic workflows into the protein realm.  Electrostatics are fundamental to ion channel function. These techniques are highly likely to prove very useful in the ion channel drug discovery arena, as more appropriate techniques for providing structure data become available e.g., CryoEM.

I make the case for information based strategies and ligand centric techniques, particularly computational workflows used by Cresset Discovery Services for customer projects, which pit the efficiency of rationality against blind trial and error.