Is structure-based drug design and toxicology ready for ion channels and transporters?

The “resolution revolution” in cryo-electron microscopy (cryo-EM) has unlocked the potential of ion channels and transporters, two of the largest classes of drug targets, for structure-based drug design and toxicology prediction. Yet, this structural bonanza comes with its own challenges not commonly encountered when dealing with more familiar, soluble protein drug targets. These include the presence of a membrane, a potential disconnect between binding and function, and ambiguous ligand and protein conformation due to low resolution.

How well can gold-standard, predictive scoring methods such as FEP+, Schrödinger’s free energy perturbation technology, perform at predicting the potency of compounds for ion channels and transporters in this context? In this webinar, we will answer this question by presenting the results of a large scale study of potency prediction for seven clinically relevant ion channels and two transporters. We will discuss how well FEP+ performs on this benchmark set, which factors critically influence accuracy, and our experiences in prospective drug discovery and toxicology settings.

Webinar highlights:

• Situations in which the inclusion of an explicit membrane in Relative Binding FEP+ simulations dramatically improved performance
• Discussion of why the OPLS5 force field led to highly accurate prospective Absolute Binding FEP+ predictions for diverse binders of a ligand-gated ion channel
• Examples from discovery programs, including on-target and off-target toxicology modeling

Who should attend? Computational chemists, toxicologists, AI drug discovery scientists, structural biologists, medicinal chemists, ion channel biologists