Ternary Kinetic Models for Rational Design of Molecular Glues

Recently, academic and industrial interest in molecular glue-based therapeutics has grown dramatically. Traditional drugs are designed to act on single targets, whereas molecular glues simultaneously bind two targets. By forming a ternary complex, molecular glues can create new therapeutic effects, such as rewiring cellular machinery to degrade specific proteins. Unfortunately, rational design of these therapies is challenging as current pharmacological theory is based on binary complex equilibria. Here, we extend our previous ternary-complex equilibrium work(JACS, 2013, 135, 6092) to derive a set of kinetic models highly analogous to Michaelis-Menten kinetics. We identify the weakest binding affinity as the most important engineerable parameter in the design of ternary-complex based therapeutics. Finally, we. have combined these equations with “big data” from new thermodynamic and kinetic databases to build interactive online tools that enable non-computational investigators to simulate their own experimental systems: • https://douglasslab.com/ternary_equilibrium/ • https://douglasslab.com/Btmax_kinetics/