Building New Bridges between In Vitro and In Vivo in Early Drug Discovery: Where Molecular Modeling Meets Systems Biology

Title:Building New Bridges between In Vitro and In Vivo in Early Drug Discovery: Where Molecular Modeling Meets Systems Biology

Volume: 17 Issue: 23

Author(s): Robert A. Pearlstein*, Daniel J.J. McKay*, Viktor Hornak, Callum Dickson, Andrei Golosov, Tyler Harrison, Camilo Velez-Vega and José Duca

Affiliation:

• Novartis Institutes for Bio- Medical Research, Inc. 181 Massachusetts Avenue, Cambridge, MA 02139,United States

• Novartis Institutes for Bio- Medical Research, Inc. 181 Massachusetts Avenue, Cambridge, MA 02139,United States

Keywords: Solvation, function, Dynamics, Non-equilibrium, Counter-balancing, Drug discovery.

Abstract: Cellular drug targets exist within networked function-generating systems whose constituent molecular species undergo dynamic interdependent non-equilibrium state transitions in response to specific perturbations (i.e.. inputs). Cellular phenotypic behaviors are manifested through the integrated behaviors of such networks. However, in vitro data are frequently measured and/or interpreted with empirical equilibrium or steady state models (e.g. Hill, Michaelis-Menten, Briggs-Haldane) relevant to isolated target populations. We propose that cells act as analog computers, “solving” sets of coupled “molecular differential equations” (i.e. represented by populations of interacting species)via “integration” of the dynamic state probability distributions among those populations. Disconnects between biochemical and functional/phenotypic assays (cellular/in vivo) may arise with targetcontaining systems that operate far from equilibrium, and/or when coupled contributions (including target-cognate partner binding and drug pharmacokinetics) are neglected in the analysis of biochemical results. The transformation of drug discovery from a trial-and-error endeavor to one based on reliable design criteria depends on improved understanding of the dynamic mechanisms powering cellular function/dysfunction at the systems level. Here, we address the general mechanisms of molecular and cellular function and pharmacological modulation thereof. We outline a first principles theory on the mechanisms by which free energy is stored and transduced into biological function, and by which biological function is modulated by drug-target binding. We propose that cellular function depends on dynamic counter-balanced molecular systems necessitated by the exponential behavior of molecular state transitions under non-equilibrium conditions, including positive versus negative mass action kinetics and solute-induced perturbations to the hydrogen bonds of solvating water versus kT.

Cite this article as:

Pearlstein A. Robert*, McKay J.J. Daniel *, Hornak Viktor , Dickson Callum , Golosov Andrei , Harrison Tyler, Velez-Vega Camilo and Duca José , Building New Bridges between In Vitro and In Vivo in Early Drug Discovery: Where Molecular Modeling Meets Systems Biology, Current Topics in Medicinal Chemistry 2017; 17 (23) . https://dx.doi.org/10.2174/1568026617666170414152311