BobPearlsteinRobert Pearlstein, PhD
(Co-Mentor: Viktor Hornak, PhD)

Global Discovery Chemistry
Cambridge, Massachusetts, United States


Our research is focused on the development of novel first principles and mechanistic theories of cellular function at the molecular and systems levels. Our overall objectives are to:

  1. Shift the drug discovery paradigm from trial-and-error screening to first principles molecular design through improved understanding of:
    1. Molecular structure vis-à-vis free energy barriers governed by water transfer energy costs
    2. Non-equilibrium dynamics vis-à-vis cellular function/dysfunction at the molecular and systems levels
    3. Pharmacodynamics vis-à-vis dynamic drug-target occupancy, pharmacokinetics, and mechanisms of cellular response.
  2. Reduce in vitro-in vivo disconnects by using integrated experimental and in silico modeling and simulation approaches that are relevant to the cellular and in vivo settings.

We study structure-kinetics relationships by using molecular dynamics simulations, together with non-linear dynamics (mass action kinetics) simulations to study steady state and non-steady state behaviors of molecular systems under non-equilibrium conditions. Our methods are implemented in novel in-house software (KinetEx and WATMD).

We are developing and testing novel first principles-based metrics in support of drug design, including solvation-based structure-kinetics relationships and efficacious non-equilibrium dynamic drug-target occupancy. Our theories and reduction to practice thereof have led to improved understanding of binding kinetics (e.g., p38α inhibition, PCSK9-LDLR binding, and antibacterial translocation through porin channels), as well as integrated drug-target binding kinetics, pharmacokinetics, and target dynamics (e.g., binding kinetics and channel gating dynamics contributions to blockade of the hERG potassium channel). Our current areas of interest include cardiac and neural action potential modeling (Markov state ion channel models) and general relationships between molecular systems architecture and cellular function.

Selected Publications

Building new bridges between in vitro and in vivo in early drug discovery: where molecular modeling meets systems biology.
Pearlstein RA, McKay D, Velez-Vega C, Hornak V, Dickson C, Golosov A, Harrison T, Duca J.
Current Topics in Medicinal Chemistry, invited submission, in preparation

Implications of dynamic occupancy, binding kinetics, and channel gating kinetics for hERG blocker safety assessment and mitigation.  
Pearlstein RA, Andrew MacCannell K, Erdemli G, Yeola S, Helmlinger G, Hu QY, Farid R, Egan W, Whitebread S, Springer C, Beck J, Wang HR, Maciejewski M, Urban L, Duca JS.
Current Topics in Medicinal Chemistry. 2016 E-Pub Ahead of Print

Contributions of water transfer energy to protein-ligand association and dissociation barriers: WaterMap analysis of a series of p38α MAP kinase inhibitors.   
Pearlstein RA, Sherman W, Abel R.
Proteins: Structure, Function, and Bioinformatics. 2013 Sep; 81:1509–1526.

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