Abstract
In this review, we outline the growing role that molecular dynamics simulation is able to play as a design tool in drug delivery. We cover both the pharmaceutical and computational backgrounds, in a pedagogical fashion, as this review is designed to be equally accessible to pharmaceutical researchers interested in what this new computational tool is capable of and experts in molecular modeling who wish to pursue pharmaceutical applications as a context for their research. The field has become too broad for us to concisely describe all work that has been carried out; many comprehensive reviews on subtopics of this area are cited. We discuss the insight molecular dynamics modeling has provided in dissolution and solubility, however, the majority of the discussion is focused on nanomedicine: the development of nanoscale drug delivery vehicles. Here we focus on three areas where molecular dynamics modeling has had a particularly strong impact: (1) behavior in the bloodstream and protective polymer corona, (2) Drug loading and controlled release, and (3) Nanoparticle interaction with both model and biological membranes. We conclude with some thoughts on the role that molecular dynamics simulation can grow to play in the development of new drug delivery systems.
Highlights
The exponential advance of the computational power available to us has led to related approaches attaining a prominent, one can argue dominant, position within pharmaceutical research
While several schemes for the development of coarse grained models have been proposed (Miyazaki et al, 2020) the two that have been most frequently used are the MARTINI potential set (Marrink et al, 2007), where the coarse grained particles are groups of ∼3 atoms with the potential sets developed based on the solubility parameters of these groups and Dissipative Particle Dynamics (DPD) (Groot and Warren, 1997; Español and Warren, 2017) where the degree of coarse graining is greater still, where the particles are soft "momentum carriers" and temperature is controlled through a thermostat designed to conserve local momentum as the effects of hydrodynamics become important at this larger length and time scale
That we have outlined the different forms of nanomedicine and the issues encountered by nanoparticles in their context as drug delivery agents, we can proceed to showcase many examples where molecular dynamics simulation, using different degrees of coarse graining, have provided mechanistic insight that complements the research program to develop new nanoparticle based drug delivery mechanisms
Summary
The exponential advance of the computational power available to us has led to related approaches attaining a prominent, one can argue dominant, position within pharmaceutical research. Drugs were found through trial and error, the search space is gigantic: the number of different small organic molecules that are theoretically possible to synthesize is ∼1063 (Bohacek et al, 1996; Hoffmann and Gastreich, 2019) a number that dwarfs such quantities as Avogadro’s number and the number of stars in the universe; drug design can be seen as searching this discrete "drug structure space." The latter half of the twentieth century saw the onset of a systematic approach to searching this space based on the "lock and key" paradigm: drug molecules were designed to fit a certain active site on a certain protein to either inhibit or activate them This was propelled by advances in three areas (1) robotics to enable massive simultaneous parallel screening experiments, (2) increasing numbers of high resolution protein structures, determined first through X-ray crystallography, but increasingly through cryo-EM, and (3) the computational power and advanced algorithms to analyze the massive data sets produced. Making a set of approximations and accepting certain limitations of the variety of phenomena that can be observed, we arrive at the molecular mechanics paradigm: the molecule modeled as a set of particles with their interactions governed by classical mechanics
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