On the other hand, the wide availability and public acceptance
of drugs also leads to their misuse. Drug overdose in patients, as
well as accumulation of drug compounds in the environment [3],
represent a further challenge to human health. The need for meth-
ods that allow rapid testing of drug presence and concentration in a
sample drives the development of biosensors, which utilize a
biological element, such as an enzyme, to facilitate the detection
of an analyte [4].
MD simulations provide a powerful tool for the investigation of
drug compounds in the context of both biological targets and
biosensing enzymes. When performed at the all-atom level of
detail, MD simulations can characterize the dynamical interactions
of drugs with their protein receptors and capture the subtle struc-
tural changes they induce, even in large biomolecular assemblies
[5]. The following chapter presents a computational protocol for
the study of protein–drug complexes with MD simulations based
on an example project and tutorial. The described approach is
broadly applicable toward elucidating mechanisms of drug action
against biological targets, designing more effective drugs com-
pounds, and engineering improved enzymes for biosensing and
bioremediation.2 Example Project: Aryl Acylamidase–Acetaminophen
Acetaminophen (N-acetyl-p-aminophenol, Fig.1) is a widely avail-
able analgesic drug commonly used to relieve pain and reduce fever.
Although it is generally regarded as the safest over the counter
analgesic when taken as directed [6, 7], i.e., in therapeutic doses,
the misuse of acetaminophen carries serious health risk. Acetamin-
ophen is metabolized by the liver, and high concentration of the
drug leads to excessive accumulation of its metabolites, which can
cause severe, even fatal liver damage [7]. Acetaminophen toxicity is
the leading cause of acute liver failure in the USA [8]. Overdose is
often unintentional, the result of misuse of formulations of other
drugs that contain acetaminophen as an additive [6]. SuccessfulFig. 1Chemical structure of the drug acetaminophen246 Jodi A. Hadden and Juan R. Perilla