Frontiers in Computational Chemistry. Volume 1

358 Pages·2015·23.25 MB·English

by  Zaheer Ul-Haq, Jeffry D. Madura

Frontiers in Computational Chemistry
(Volume 1)
Edited By
Zaheer-ul-Haq
Panjwani Center for Molecular Medicine & Drug Research
International Center for Chemical & Biological Sciences
University of Karachi
Pakistan
&
J. D. Madura
Department of Chemistry & Biochemistry
Center for Computational Sciences
Duquesne University, Pittsburgh
USA
Elsevier
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ISBN: 978-1-60805-865-5
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CONTENTS
Preface i
List of Contributors iii
CHAPTERS
1. Computational Strategies to Incorporate GPCR Complexity in Drug Design 3
Maria Marti-Solano, Agnieszka A. Kaczor, Ramon Guixà-González and Jana Selent
2. Knowledge-Based Drug Repurposing: A Rational Approach Towards the
Identification of Novel Medical Applications of Known Drugs 44
Carolina L. Bellera, Mauricio E. Di Ianni, María L. Sbaraglini, Eduardo A. Castro, Luis E.
Bruno-Blanch and Alan Talevi
3. Tuning the Solvation Term in the MM-PBSA/GBSA Binding Affinity Predictions 82
Irene Maffucci and Alessandro Contini
4. Recent Advances in the Discovery and Development of Protein-Protein
Interaction Modulators by Virtual Screening 121
Dik-Lung Ma, Li-Juan Liu, Sheng Lin, Modi Wang, Daniel Shiu-Hin Chan and Chung-Hang
Leung
5. Computational Design of Biological Systems: From Systems to Synthetic Biology 158
Milsee Mol and Shailza Singh
6. Considering the Medium when Studying Biologically Active Molecules:
Motivation, Options and Challenges 197
Liliana Mammino and Mwadham M. Kabanda
7. A Novel Coarse-Grained Description of Protein Structure and Folding by UNRES
Force Field and Discrete Nonlinear Schrödinger Equation 257
Adam Liwo, Antti Niemi, Xubiao Peng and Adam K. Sieradzan
8. Computational Chemistry Strategies Tackling Function and Inhibition of
Pharmaceutically Relevant Targets 290
Michele Cascella, Matteo Dal Peraro and Marco De Vivo
Subject Index 344
i
PREFACE
Computational chemistry is a very diverse field spanning from the development and application of
linear free energy relationships (e.g. QSAR, QSPR), to electronic structure calculations, molecular
dynamics simulations, and to solving coupled differential equations (e.g. drug metabolism). The
focus of Frontiers in Computational Chemistry is to present material on molecular modeling
techniques used in drug discovery and the drug development process. Topics falling under this
umbrella include computer aided molecular design, drug discovery and development, lead
generation, lead optimization, database management, computer and molecular graphics, and the
development of new computational methods or efficient algorithms for the simulation of chemical
phenomena including analyses of biological activity. In this volume, we have collected eight
different perspectives in the application of computational methods towards drug design.
In chapter 1 “Computational Strategies to Incorporate GPCR Complexity in Drug Design” the
authors review various computational approaches to G protein-coupled receptors (GPCRs). They
review the use of GPCR databases to extract starting information about the structure and function
of these systems. The authors also review different strategies currently being probe the molecular
mechanisms of drug action as well as the development of new drugs.
The topic of chapter 2 “Knowledge-Based Drug Repurposing: A Rational Approach Towards the
Identification of Novel Medical Applications of Known Drugs” is of current interest in the
pharmaceutical industry. As we learn more about the biochemical pathways and the interactions of
compounds with proteins of these pathways, one can gain an appreciation of how current and
previous drugs can be used for other medical uses. This chapter discusses the use of
cheminformatics and bioinformatics in identifying new insights about known drugs.
Chapter 3, “Tuning the Solvation Term in the MM-PBSA/GBSA Binding Affinity Predictions”
focuses on the development and application of a computational tool. A widely used method,
Molecular Mechanics Poisson-Boltzmann (Generalized Born) Surface Area (MM-PBSA, MM-
GBSA), is discussed in terms of applying the method to calculate accurate binding affinities. The
authors point out that in order to obtain good, reliable results the MM-PBSA or MM-GBSA
methods need to be tuned for a particular system. In particular, they focus on interior dielectric
constant as well as the PB and GB solvers.
A very active area of experimental and computational research is protein-protein interactions that
is the topic of Chapter 4, “Recent Advances in the Discovery and Development of Protein-Protein
Interaction Modulators by Virtual Screening”. In particular, the application of virtual screening
methods to find compounds that modulate protein-protein interactions. This is a very challenging
task since protein interfaces are flat, large, and lack distinct features. The authors provide a review
of the use of virtual screening in protein-protein interactions as its role in drug discovery.
Across the scientific field, we come across the term “big data.” In particular, that data generated
from genomic projects is overwhelming. In Chapter 5 “Computational Design of Biological
Systems: From Systems to Synthetic Biology” the authors describe the development and use of
computational methods on large biological data sets to potentially engineer circuits. This systems
ii
biology approach to understanding biological function is being used to develop synthetic
biological systems. Such developments have potential uses in biotechnology and in the
development of strategies to treat various diseases such as cancer.
Biological systems are complex systems to study. In Chapter 6, “Considering the Medium when
Studying Biologically Active Molecules: Motivation, Options and Challenges” we are reminded
that when studying biological systems not to forget the environment surrounding the system. Most
of the time, the environment is left out due to its complexity; however, one must keep in mind that
the environment may play a significant role in biological activity. The authors review some insight
into how to appropriately include the environment into the study of a particular biological system.
As computational power, hardware and software, continue to increase so do the systems, both
temporally and spatially. One approach to address the increase in systems is presented in Chapter
7 “New frontiers of coarse-grained approach to protein folding.” Coarse-graining involves the
reduction in the number of particles of the system by representing a small group of particles, e.g.
an amino side-chain by a single particle. This reduction in the number of particles to represent a
biological system has the potential to allow for greater exploration of the free energy landscape as
well as simulation increased timescales. The authors review the use of coarse-graining in the study
of protein folding.
The last chapter “Computational chemistry strategies-tackling function and inhibition of
pharmaceutically relevant targets” reviews the various computational methods used to identify
pharmaceutically relevant targets. The authors illustrate the application of various tools from first
principles to empirical methods in the discovery and development of new compounds that
potentially lead or become the next drug. They appropriately point out that it is through the
combination of experiment and computations that lead to significant advancement in molecular
medicine.
Zaheer-ul-Haq
Panjwani Center for Molecular Medicine & Drug Research
International Center for Chemical & Biological Sciences
University of Karachi
Pakistan
&
J. D. Madura
Department of Chemistry & Biochemistry
Center for Computational Sciences
Duquesne University, Pittsburgh
USA
iii
List of Contributors
Adam K. Sieradzan Faculty of Chemistry, University of Gdańsk, Wita Stwosza 63, 80-952
Gdańsk, Poland and Department of Physics and Astronomy and Science
for Life Laboratory, Uppsala University, P.O. Box 803, S-75108
Uppsala, Sweden
Adam Liwo Faculty of Chemistry, University of Gdańsk, Wita Stwosza 63, 80-952
Gdańsk, Poland
Agnieszka A. Kaczor University of Eastern Finland, School of Pharmacy, Department of
Pharmaceutical Chemistry, Kuopio, Finland and Department of
Synthesis and Chemical Technology of Pharmaceutical Substances,
Faculty of Pharmacy with Division for Medical Analytics, Medical
University of Lublin, Lublin, Poland
Alan Talevi Medicinal Chemistry, Department of Biological Sciences, Faculty
of Exact Sciences, National University of La Plata, Buenos Aires,
Argentina
Alessandro Contini Dipartimento di Scienze Farmaceutiche - Sezione di Chimica Generale
e Organica “Alessandro Marchesini”, Università degli Studi di Milano,
Via Venezian, 21 20133 Milano, Italy
Antti Niemi Department of Physics and Astronomy and Science for Life Laboratory,
Uppsala University, P.O. Box 803, S-75108 Uppsala, Sweden and
Laboratoire de Mathematiques et Physique Theorique CNRS UMR
6083, Fédération Denis Poisson, Université de Tours, Parc de
Grandmont, F37200 Tours, France and Department of Physics, Beijing
Institute of Technology, Haidian District, Beijing 100081, People’s
Republic of China
Carolina L. Bellera Medicinal Chemistry, Department of Biological Sciences, Faculty of
Exact Sciences, National University of La Plata, Buenos Aires,
Argentina
Chung-Hang Leung State Key Laboratory of Quality Research in Chinese Medicine,
Institute of Chinese Medical Sciences, University of Macau, Macao,
China
Daniel Shiu-Hin Chan Department of Chemistry, Hong Kong Baptist University, Kowloon
Tong, Hong Kong, China
Dik-Lung Ma Department of Chemistry, Hong Kong Baptist University, Kowloon
Tong, Hong Kong, China
Eduardo A. Castro Institute of Physicochemical Theoretical and Applied Research
(INIFTA), National Council of Scientific and Technical Research
(CONICET) CCT La Plata, Buenos Aires, Argentina
Irene Maffucci Dipartimento di Scienze Farmaceutiche - Sezione di Chimica Generale
e Organica “Alessandro Marchesini”, Università degli Studi di Milano,
iv
Via Venezian, 21 20133 Milano, Italy
Jana Selent Research Programme on Biomedical Informatics (GRIB), Department
of Experimental and Health Sciences, Universitat Pompeu Fabra, IMIM
(Hospital del Mar Medical Research Institute), Barcelona, Spain
Li-Juan Liu State Key Laboratory of Quality Research in Chinese Medicine,
Institute of Chinese Medical Sciences, University of Macau, Macao,
China
Liliana Mammino Department of Chemistry, University of Venda, South Africa
Luis E. Bruno-Blanch Medicinal Chemistry, Department of Biological Sciences, Faculty of
Exact Sciences, National University of La Plata, Buenos Aires,
Argentina
Marco De Vivo Drug Discovery and Development, Italian Institute of Technology,
Genoa, Italy
María L. Sbaraglini Medicinal Chemistry, Department of Biological Sciences, Faculty of
Exact Sciences, National University of La Plata, Buenos Aires,
Argentina
Maria Marti-Solano Research Programme on Biomedical Informatics (GRIB), Department
of Experimental and Health Sciences, Universitat Pompeu Fabra, IMIM
(Hospital del Mar Medical Research Institute), Barcelona, Spain
Matteo Dal Peraro Institute of Bioengineering, School of Life Sciences,
ÉcolePolytechniqueFédérale de Lausanne (EPFL), Lausanne,
Switzerland and Swiss Institute of Bioinformatics (SIB), Lausanne,
Switzerland
Mauricio E. Di Ianni Medicinal Chemistry, Department of Biological Sciences, Faculty of
Exact Sciences, National University of La Plata, Buenos Aires,
Argentina
Michele Cascella Department of Chemistry and Centre for Theoretical and Computational
Chemistry (CTCC), University of Oslo, Oslo, Norway;
Milsee Mol National Centre for Cell Science, NCCS Complex, Ganeshkhind, Pune
University Campus, Pune 411007, India
Modi Wang Department of Chemistry, Hong Kong Baptist University, Kowloon
Tong, Hong Kong, China
Mwadham M. Kabanda Department of Chemistry, North-West University (Mafikeng Campus),
South Africa
Rafik Karaman Bioorganic Chemistry Department, Faculty of Pharmacy Al-Quds
University, P.O. Box 20002, Jerusalem, Palestine
Ramon Guixà-González Research Programme on Biomedical Informatics (GRIB), Department
of Experimental and Health Sciences, Universitat Pompeu Fabra, IMIM
(Hospital del Mar Medical Research Institute), Barcelona, Spain
v
Shailza Singh National Centre for Cell Science, NCCS Complex, Ganeshkhind, Pune
University Campus, Pune 411007, India
Sheng Lin Department of Chemistry, Hong Kong Baptist University, Kowloon
Tong, Hong Kong, China
Xubiao Peng Department of Physics and Astronomy and Science for Life Laboratory,
Uppsala University, P.O. Box 803, S-75108 Uppsala, Sweden
Frontiers in Computational Chemistry, Vol. 1, 2015, 3-43 3
CHAPTER 1
Computational Strategies to Incorporate GPCR Complexity in
Drug Design
Maria Marti-Solano1, Agnieszka A. Kaczor2,3,*, Ramon Guixà-González1 and
Jana Selent1,*
1Research Programme on Biomedical Informatics (GRIB), Department of
Experimental and Health Sciences, Universitat Pompeu Fabra, IMIM (Hospital
del Mar Medical Research Institute), Barcelona, Spain; 2University of Eastern
Finland, School of Pharmacy, Department of Pharmaceutical Chemistry, Kuopio,
Finland and 3Department of Synthesis and Chemical Technology of Pharmaceutical
Substances, Faculty of Pharmacy with Division for Medical Analytics, Medical
University of Lublin, Lublin, Poland
Abstract: G protein-coupled receptors (GPCRs) represent the most important family of
drug targets to date. However, state-of-the-art experimental procedures, able to
characterize in deep both GPCR modulation in health and disease and the molecular
mechanisms of drug action at these receptors, have provided a more nuanced picture
than previously expected. Several aspects of GPCR function, which are currently being
characterized, clarify some regulatory processes regarding these receptors and, at the
same time, introduce novel levels of complexity which should be taken into
consideration for rational drug design. In this scenario, computational approaches can
help in several ways rationalize the increasing amount of data on GPCRs and their
ligands. On the one hand, a set of databases devoted to these receptors provide excellent
starting points for data mining. On the other, exploitation of the ever-increasing ligand
and structure-based information by novel computational techniques can help addressing
emerging questions in the GPCR field. Some of these questions comprise the refined
modulation of GPCR signaling states by biased agonists, the exploitation of GPCR
oligomers as drug targets, the analysis of polypharmacology in GPCR ligands, the
development of strategies for receptor deorphanization or the prediction of off-target
interactions of known drugs targeting these receptors. In this chapter, we will cover
some of these strategies for knowledge-based rational design for GPCRs and will
discuss the main hurdles which they may need to overcome to yield novel, safer and
more efficacious drugs possessing polished mechanisms of action.
*Corresponding author Jana Selent: Research Programme on Biomedical Informatics (GRIB), Department
of Experimental and Health Sciences, Universitat Pompeu Fabra, IMIM (Hospital del Mar Medical Research
Institute), Dr. Aiguader 88, E-08003 Barcelona (Spain) / University of Eastern Finland, School of Pharmacy,
Department of Pharmaceutical Chemistry, Yliopistoranta 1, P.O. Box 1627, FI-70211 Kuopio, Finland;
Tel/Fax: [phone]; E-mail: [email protected]
Agnieszka A. Kaczor: Medical University of Lublin, Faculty of Pharmacy with Division for Medical
Analytics, Department of Synthesis and Chemical Technology of Pharmaceutical Substances, 4A Chodzki
St., 20093 Lublin, Poland; Tel: [phone]; Fax: [phone]; E-mail: [email protected]
Zaheer-ul-Haq and J. D. Madura (Eds)
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