Abstract
We review the use of molecular dynamics (MD) simulation as a drug design tool in the context of the role that the lipid membrane can play in drug action, i.e., the interaction between candidate drug molecules and lipid membranes. In the standard “lock and key” paradigm, only the interaction between the drug and a specific active site of a specific protein is considered; the environment in which the drug acts is, from a biophysical perspective, far more complex than this. The possible mechanisms though which a drug can be designed to tinker with physiological processes are significantly broader than merely fitting to a single active site of a single protein. In this paper, we focus on the role of the lipid membrane, arguably the most important element outside the proteins themselves, as a case study. We discuss work that has been carried out, using MD simulation, concerning the transfection of drugs through membranes that act as biological barriers in the path of the drugs, the behavior of drug molecules within membranes, how their collective behavior can affect the structure and properties of the membrane and, finally, the role lipid membranes, to which the vast majority of drug target proteins are associated, can play in mediating the interaction between drug and target protein. This review paper is the second in a two-part series covering MD simulation as a tool in pharmaceutical research; both are designed as pedagogical review papers aimed at both pharmaceutical scientists interested in exploring how the tool of MD simulation can be applied to their research and computational scientists interested in exploring the possibility of a pharmaceutical context for their research.
Highlights
In the most breathtaking giant leap forward in life science since the determination of the double helix structure of DNA, the general structure from the sequence problem has been solved for the case of an individual protein domain [1]
In our previous review paper [3], part 1 of this series, we presented many examples of how molecular dynamics (MD) simulation has been used as a tool to provide mechanistic insight relevant to drug delivery and how this insight has been used, in concrete practical terms; we continue the discussion of the role MD simulation has and will continue to play in pharmaceutical research, focusing, in this review paper, on its role in drug design, covering its ability to elucidate a central element left out of the conventional drug design paradigm: lipid membranes
Through a detailed discussion of how MD simulation can be used to elucidate the roles the interaction with lipid membranes play in drug action, we hope we have provided the reader with an intuitive understanding of the broader landscape within which drug molecules act, beyond the limiting paradigm of ADME and “docking and scoring”
Summary
In the most breathtaking giant leap forward in life science since the determination of the double helix structure of DNA, the general structure from the sequence problem has been solved for the case of an individual protein domain [1]. While previous review papers have shown how MD simulation has helped elucidate the role the lipid membrane plays in substrate and drug selection for membrane proteins [28,29,30,31,32], drug membrane interactions [33,34,35,36,37,38,39,40,41], drug delivery [3,42,43,44,45], antimicrobial peptides [46,47,48,49,50,51,52,53,54], and methodologies [28,55,56,57,58,59,60], this is the first review paper, that we are aware of, focusing on the entirety of the use of MD simulation to incorporate the role played by interactions with lipid membranes in drug design This can be seen, in turn, as a case study of the potential for MD simulation to expand the paradigm of drug design to all aspects of the broader biophysical environment within which drug action occurs.
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