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CONTRIBUTORS

Leonidas Alexopoulos*
School of Mechanical Engineering, National Technical University of Athens, Athens,
Greece. ProtAtonce Ltd., Athens, Greece
Shabana Kouser Ali
Medical Biotechnology Division, School of Biosciences and Technology, VIT University,
Vellore, Tamil Nadu, India
Jane P.F. Bai
Office of Clinical Pharmacology, Office of Translational Science, Center for Drug
Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland,
USA
Sandya R. Beeram
Department of Chemistry, University of Nebraska-Lincoln, Lincoln, Nebraska, USA
Cong Bi
Department of Chemistry, University of Nebraska-Lincoln, Lincoln, Nebraska, USA
Mohammad Bohlooly
Astrazeneca, Discovery Sciences, Reagents and Assay Development, Transgenics Group,
Molndal, Sweden
Ilse Du Preez
School for Physical and Chemical Sciences, Human Metabolomics, North-West University,
Potchefstroom, South Africa
C. George Priya Doss
Medical Biotechnology Division, School of Biosciences and Technology, VIT University,
Vellore, Tamil Nadu, India
Ellen Y. Guo
Molecular and Cellular Biology, Liberal Arts and Sciences, University of Illinois at Urbana–
Champaign, Urbana–Champaign, Illinois, USA
David S. Hage
Department of Chemistry, University of Nebraska-Lincoln, Lincoln, Nebraska, USA
Junguk Hur
Department of Biomedical Sciences, School of Medicine & Health Sciences, University of
North Dakota, Grand Forks, North Dakota, USA
Kewal K. Jain
Jain PharmaBiotech, Basel, Switzerland

*Present address: School of Mechanical Engineering, National Technical University of Athens, Athens,
Greece.

ix
x Contributors

Nadia Koen
School for Physical and Chemical Sciences, Human Metabolomics, North-West University,
Potchefstroom, South Africa
Zhao Li
Department of Chemistry, University of Nebraska-Lincoln, Lincoln, Nebraska, USA
Du Toit Loots
School for Physical and Chemical Sciences, Human Metabolomics, North-West University,
Potchefstroom, South Africa
Ioannis N. Melas
Astrazeneca, Discovery Sciences, Group of Quantitative Biology, Molndal, Sweden
V.S. Priyadharshini
Instituto Nacional de Enfemedades Respiratorias, Delegación Tlalpan, Mexico
Theodore Sakellaropoulos†
Office of Clinical Pharmacology, Office of Translational Science, Center for Drug
Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland,
USA
Donald R.J. Singer
Fellowship of Postgraduate Medicine, London, United Kingdom
P. Sneha
Medical Biotechnology Division, School of Biosciences and Technology, VIT University,
Vellore, Tamil Nadu, India
D. Suresh‡
Department of Chemistry, University of Nebraska-Lincoln, Lincoln, Nebraska, USA
S.A. Syed Haneef
Medical Biotechnology Division, School of Biosciences and Technology, VIT University,
Vellore, Tamil Nadu, India
Luis M. Teran
Instituto Nacional de Enfemedades Respiratorias, Delegación Tlalpan, Mexico
D. Thirumal Kumar
Medical Biotechnology Division, School of Bioscience and Technology, VIT University,
Vellore, Tamil Nadu, India
Zoulikha M. Zaı̈r
Warwick Medical School, University of Warwick, Coventry, United Kingdom
Xiwei Zheng
Department of Chemistry, University of Nebraska-Lincoln, Lincoln, Nebraska, USA

†
Present address: School of Mechanical Engineering, National Technical University of Athens, Athens,
Greece.
‡
Home department: Department of Chemistry, Tumkur University, Tumakuru, Karnataka, India.
PREFACE

Personalized medicine encompasses the use of biological information for

each patient in order to provide customized health care tailored to the indi-
vidual patient. Such an individualized approach for medical decisions,
practices, and treatment became clearly necessary due to a number of obser-
vations. For instance, the course of disease differs from one person to
another. The effects of drugs used for treatment of a disease also vary largely
between different patients. It is now well established that individual differ-
ences between patients, such as genetic polymorphisms, have significant
effect on the onset of diseases as well as on absorption of drugs and their
metabolism in patient’s body. Personalized medicine takes such variations
into account and tries to take advantage of them. It is believed that such cus-
tomized therapies will improve patients’ response rates to the treatment
while reducing significantly any adverse effects the drugs might have.
Personalized medicine is based on the dynamics of systems biology and
uses predictive tools to evaluate health risks and to design personalized health
plans to help patients to minimize risks, prevent disease, and to treat it with
precision when it occurs. Some of the most contemporary and very prom-
ising tools employed in personalized treatment of patients are discussed in
the first three chapters of this volume. First chapter discusses the general
principles of high-performance affinity chromatography and the various
approaches that have been used in this technique to examine drug–protein
binding and in work related to personalized medicine. This technique is a
great asset to personalized medicine because the binding of drugs with pro-
teins and other agents in serum can affect the dosage and action of drugs. The
extent of this binding may also vary with a given disease state. Second article
in this thematic volume focuses on the advances in proteomic technologies
that have made important contribution to the development of personalized
medicine by facilitating detection of protein biomarkers, proteomics-based
molecular diagnostics as well as protein biochips and pharmacoproteomics.
Application of nanobiotechnology in proteomics, nanoproteomics, has fur-
ther enhanced applications in personalized medicine. Proteomics has already
proved to be a good bridge between diagnostics and design of therapeutics.
The integration of last two processes shows to be of a great importance for
advancing personalized medicine. The third chapter in this volume reviews
in detail metabolomics as a tool used in personalized medicine.

xi
xii Preface

Metabolomics is the newest addition to the “omics” domain and the closest
to the observed phenotype. It reflects changes occurring at all molecular
levels, as well as influences resulting from other internal and external factors.
By comparing the metabolite profiles of two or more disease phenotypes,
metabolomics can be applied to identify biomarkers related to the perturba-
tion being investigated. These biomarkers can, in turn, be used to develop
personalized prognostic, diagnostic, and treatment approaches, and can also
be applied to the monitoring of disease progression, treatment efficacy,
predisposition to drug-related side effects, and potential relapse.
The fourth chapter discusses the importance of a range of new
approaches to developing new and reprofiled medicines to treat common
and serious diseases, and rare diseases: new network pharmacology
approaches, adaptive trial designs with enriched populations more likely
to respond safely to treatment, as assessed by companion diagnostics for
response and toxicity risk and use of “real-world” data. Case studies are
described of single and multiple protein–drug targets in several important
therapeutic areas. These case studies also illustrate the value and complexity
in use of selective biomarkers of clinical response and risk of adverse drug
effects, either singly or in combination.
Chapters 5 and 6 in this volume give in-depth analyses of applying the
tools of personalized medicine in some of the most common diseases. The
fifth article in this volume highlights the contributions of proteomics toward
the understanding of personalized medicine in respiratory disease and its
potential applications in the clinic. The sixth chapter is focused on the chal-
lenges of treating different cancer types, which behave like moving targets
due to mutation and evolution, and the current state-of-the-art research
in this area. A special emphasis is made on the computational approaches
to accelerating novel medicine and better personalized patient care from
bedside to benchtop.
Chapter 7 in this volume focuses on high-end computational methods,
such as molecular dynamics (MD) simulation that has proved to be a con-
stitutive approach for detecting the minor changes associated with single
nucleotide polymorphisms (SNPs) in nucleic acids for better understanding
of their role in protein structural and functional alterations. MD along with
docking analysis can reveal the synergetic effect of an SNP in protein–ligand
interaction and provides a foundation for designing a particular drug mol-
ecule for an individual. This compelling application of computational power
and the advent of other technologies have paved a promising way toward
personalized medicine. In the Eighth article of this thematic volume,
Preface xiii

authors discuss the available clinical strategies and different methods how
pharmacological chaperones can be personalized and used as a next-
generation approach to address different lysosomal storage disorders.
The final two chapters in this volume exemplify the applicability of
molecular modeling and simulation approaches in personalized medicine
by exploring the inhibitory activity of Wortmannin toward oncogenic
mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic sub-
unit alpha (PIK3CA) (Chapter 9), and the importance of mutations in
A1-domain of von Willebrand factor (VWD) gene for the structural and
functional alterations related to thrombosis, compared to the native
VWD protein (Chapter 10).
The aim of this volume is to promote further research and development
in the design of new personalized therapeutics and treatments using biolog-
ical information for each patient via translation of recent genomic, genetic,
proteomics, and metabolomics advances into clinical context.

DR. ROSSEN DONEV

Biomed Consult Ltd
United Kingdom
 CHAPTER ONE

High-Performance Affinity
Chromatography: Applications in
Drug–Protein Binding Studies and
Personalized Medicine
Zhao Li, Sandya R. Beeram, Cong Bi, D. Suresh1, Xiwei Zheng,
David S. Hage2
Department of Chemistry, University of Nebraska-Lincoln, Lincoln, Nebraska, USA
2
Corresponding author: e-mail address: [email protected]

Contents
1. Introduction 2
1.1 Drug–Protein Interactions in Blood 4
1.2 Preparation of HPAC Columns for Drug–Protein Binding Studies 7
2. Frontal Analysis Studies of Drug–Protein Interactions 10
2.1 General Principles of Frontal Analysis 10
2.2 Characterization of Simple Interactions by Frontal Analysis 13
2.3 Characterization of Complex Interactions by Frontal Analysis 15
3. Zonal Elution Studies of Drug–Protein Interactions 17
3.1 General Principles of Zonal Elution 17
3.2 Characterization of Drug–Protein Interactions by Zonal Elution 21
4. Other Methods for Examining Drug–Protein Interactions 22
4.1 Peak Decay Method 22
4.2 Ultrafast Affinity Extraction 25
4.3 Chromatographic Immunoassays 28
5. Conclusion 30
Acknowledgments 31
References 31

Abstract
The binding of drugs with proteins and other agents in serum is of interest in person-
alized medicine because this process can affect the dosage and action of drugs. The
extent of this binding may also vary with a given disease state. These interactions
may involve serum proteins, such as human serum albumin or α1-acid glycoprotein,
or other agents, such as lipoproteins. High-performance affinity chromatography

1
Home department: Department of Chemistry, Tumkur University, Tumakuru, Karnataka, India.

Advances in Protein Chemistry and Structural Biology, Volume 102 # 2016 Elsevier Inc. 1
ISSN 1876-1623 All rights reserved.
http://dx.doi.org/10.1016/bs.apcsb.2015.09.007
2 Zhao Li et al.

(HPAC) is a tool that has received increasing interest as a means for studying these inter-
actions. This review discusses the general principles of HPAC and the various
approaches that have been used in this technique to examine drug–protein binding
and in work related to personalized medicine. These approaches include frontal analysis
and zonal elution, as well as peak decay analysis, ultrafast affinity extraction, and chro-
matographic immunoassays. The operation of each method is described and examples
of applications for these techniques are provided. The type of information that can be
obtained by these methods is also discussed, as related to the analysis of drug–protein
binding and the study of clinical or pharmaceutical samples.

1. INTRODUCTION
Personalized medicine is a field of healthcare in which the treatment of
an individual is based on information related to their clinical status, genetics,
or environment (Gunsburg & Willard, 2009; Ziegler, Koch,
Krockenberger, & Grobhennig, 2012). The overall goal of personalized
medicine is to optimize the medical care and outcome for an individual
(Gunsburg & Willard, 2009). Work in this area has been carried out to pro-
mote the health and wellness of a patient by aiding in disease prevention,
assist in the detection of disease, and optimize the selection of treatment
for a patient. As a result of these possible applications, this field is believed
to hold great promise in the future of medicine and healthcare (Buchner,
Blonski, & Lichtenstein, 2011; Cottone, Orlando, & Renna, 2010;
Gunsburg & Willard, 2009; Trusheim, Berndt, & Douglas, 2007).
One area that has been of interest in personalized medicine is in how the
dosage and action of drugs may vary from one person to the next or between
healthy individuals and those with a given disease (Gunsburg & Willard,
2009; Ziegler et al., 2012). A process that can affect the apparent dosage
of many pharmaceutical agents is the binding of drugs with proteins and
other carrier agents in blood. This binding may involve serum proteins, such
as human serum albumin (HSA) or α1-acid glycoprotein (AGP), or other
agents, such as lipoproteins. This process is significant for many drugs, with
43% of the 1500 most common drugs being at least 90% bound in serum
(Kratochwil, Huber, Muller, Kansy, & Gerber, 2002). This binding can
influence the eventual activity and fate of drugs once they have entered
the circulation and plays a central role in determining the absorption, distri-
bution, and rate of excretion or metabolism of many drugs in the blood-
stream (Hage, 2002; Kwong, 1985; Lindup, 1987; Peters, 1996).
High-Performance Affinity Chromatography in Personalized Medicine 3

High-performance affinity chromatography (HPAC) is a tool that has

received increasing interest in recent years as a means of studying and char-
acterizing drug interactions with serum proteins (Hage et al., 2009; Kim &
Wainer, 2008; Schiel & Hage, 2009). This method is a type of high-
performance liquid chromatography (HPLC) that uses an immobilized
binding agent (e.g., a serum protein) as the stationary phase (Hage et al.,
2009). The basic components of HPAC are shown in Fig. 1. In this tech-
nique, the binding agent is immobilized onto a chromatographic support,
which is suitable for use in HPLC, and is placed into a column. This column
and support can be used to bind and retain drugs that interact with the bind-
ing agent. The resulting elution profile can then be used to provide infor-
mation on the strength, rate, and nature of the drug’s interaction with the
binding agent (Hage et al., 2009; Kim & Wainer, 2008; Schiel &
Hage, 2009).
There are several features that have made HPAC of interest for drug–
protein binding studies. For instance, this method has good precision, is rel-
atively fast, and is easy to automate (Hage, 2001). It can also be used with
many types of detectors and has been shown in numerous studies to provide
good correlation with reference methods when it is used to study drug
interactions with serum proteins. Another useful feature of HPAC is its
ability to often reuse the same protein or binding agent for a large number
of experiments, with even hundreds of studies being possible in some cases
(Hage et al., 2009; Kim & Wainer, 2008; Schiel & Hage, 2009).
This review will discuss the principles of HPAC and of the methods that
have been used in this technique to examine drug interactions with serum
binding agents. Various applications of these methods will be presented as

Figure 1 General components of a system for carrying out high-performance affinity

chromatography. The squares represent nonretained or weakly retained components
of the original sample, and the circles represent more strongly retained sample
components.
4 Zhao Li et al.

related to personalized medicine and drug–protein binding studies. These

examples will include the use of HPAC to examine simple or complex inter-
actions between drugs and serum proteins or other binding agents. The type
of information that can be provided by each technique will be discussed, and
the use of each method with clinical or pharmaceutical samples will be
considered.

1.1 Drug–Protein Interactions in Blood

Drugs can bind to various proteins and agents in the bloodstream. One protein
that acts as a binding agent for many drugs and small solutes in blood is HSA
(Lindup, 1987; Mohamadi-Nejad, Moosavi-Movahedi, Hakimelahi, &
Sheibani, 2002; Peters, 1996). HSA, whose structure is shown in Fig. 2A,
is the most abundant protein in serum and has a normal concentration that
ranges from 30 to 50 g/L (Peters, 1996; Tietz, 1986). This protein has a molar
mass of 66.5 kDa and consists of a single chain of 585 amino acids with
17 internal sulfide bonds (Peters, 1996). This protein has various roles, includ-
ing its action to help regulate osmotic pressure and control pH in the blood-
stream (Fanali et al., 2012; Peters, 1996; Wang et al., 2008). HSA also acts as a
transport protein for a large number of low mass substances within blood,
including some hormones, fatty acids, and many drugs (Barzegar et al.,
2007; Ghuman et al., 2005; Herve, Urien, Albengres, Duche, &
Tillement, 1994; Lindup, 1987; Mohamadi-Nejad et al., 2002; Peters,
1996; Seedher & Kanojia, 2008; Vidal, Nielsen, & Welinder, 1992).

Figure 2 (A) Structure of human serum albumin (HSA), including the locations of the
two major drug-binding sites on this protein (i.e., Sudlow sites I and II), and (B) the gen-
eral structure of a lipoprotein. The structure in (A) was generated by using PDB file 2BXD
and includes a molecule of warfarin that is bound at Sudlow site I (Ghuman et al., 2005).
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