Death by a thousand cuts through kinase inhibitor combinations that maximize selectivity and enable rational multitargeting

Outhwaite IR, Singh S, Berger B-T, Knapp S, Chodera JD, Seeliger MA
eLife 12:e86189, 2024 [DOI] [bioRxiv] [GitHub]

We show how combinations of kinase inhibitors can achieve selectivity gains for rational kinase polypharmacology.

Identifying and Overcoming the Sampling Challenges in Relative Binding Free Energy Calculations of a Model Protein:Protein Complex

Zhang I, Rufa DA, Pulido I, Henry MM, Rosen LE, Hauser K, Singh S, Chodera JD
Journal of Chemical Theory and Computation 19:4863, 2023

We assess what is required for alchemical free energy calculations to be able to make high-quality predictions of the impact of interfacial mutations on protein-protein binding.

MEN1 mutations mediate clinical resistance to menin inhibition

Perner F, Stein EM, Wenge DV, Singh S, Kim J, Apazidis A, Rahnamoun H, Anand D, Marinaccio C, Hatton C, Wen Y, Stone RM, Schaller D, Mowla S, Xiao W, Gamlen HA, Stonestrom AJ, Persaud S, Ener E, Cutler JA, Doench JG, McGeehan GM, Volkamer A, Chodera JD, Nowak RP, Fischer ES, Levine RL, Armstrong SA, Cai SF
Nature 615:913, 2023 [DOI]

We describe how mutants that confer therapeutic resistance to menin inhibition impact small molecule binding but not interactions with the natural ligand MLL1.