Fragment-Based Methods in Drug Discovery

227 Pages·2015·9.394 MB·English

by  Anthony E. Klon (eds.)

Methods in
Molecular Biology 1289
Anthony E. Klon Editor
Fragment-Based
Methods in
Drug Discovery
M M B
ETHODS IN OLECULAR IOLOGY
Series Editor
John M. Walker
School of Life and Medical Sciences
University of Hertfordshire
Hatfield, Hertfordshire, AL10 9AB , UK
For further volumes:
http://www.springer.com/series/7651

Fragment-Based Methods
in Drug Discovery
Edited by
Anthony E. K lon
Pennsylvania Drug Discovery Institute, Doylestown, PA, USA
Editor
Anthony E . Klon
Pennsylvania Drug Discovery Institute
Doylestown, PA, USA
ISSN 1064-3745 ISSN 1940-6029 (electronic)
Methods in Molecular Biology
ISBN 978-1-4939-2485-1 ISBN 978-1-4939-2486-8 (eBook)
DOI 10.1007/978-1-4939-2486-8
Library of Congress Control Number: 2015931254
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Prefa ce
Fragment-based methods for drug discovery have been investigated in one form or another
for several decades, but there has been increased interest in the last 10 years in their practi-
cal application in drug discovery. This is partly due to some of the recent successes of the
fi eld and their contribution to drug discovery, as well as an expansion in the number and
availability of methods and improved computational resources. This volume will cover the
techniques necessary for a successful fragment-based drug design project, beginning from
defi ning the problem in terms of preparing the protein model, identifying potential binding
sites, and the consideration of various candidate fragments for simulation. The second part
of this volume discusses the technical aspects that various methods have used to simulate
fragment binding to a target protein using Monte Carlo, molecular dynamics, and docking
algorithms. After simulations, fragments are assembled into molecules using a variety of
approaches, which are explored next. A discussion of design strategies and consideration of
drug-like properties is included as part of the design process at this stage. Finally, several
examples of successful fragment-based drug design projects are presented.
Doylestown, PA Anthony E. K lon
v

Contents
Preface. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v
Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . i x
PART I PREPARATION
1 Solvation Methods for Protein–Ligand Docking . . . . . . . . . . . . . . . . . . . . . . . 3
Rachelle J. Bienstock
2 Binding Site Druggability Assessment in Fragment-Based Drug Design. . . . . . 1 3
Yu Z hou and Niu Huang
3 G enerating “Fragment-Based Virtual Library” Using Pocket Similarity
Search of Ligand–Receptor Complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 3
Raed S . K hashan
4 Virtual Fragment Preparation for Computational Fragment-B ased
Drug Design. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Jennifer L . L udington
5 Fragment Library Design: Using Cheminformatics and Expert Chemists
to Fill Gaps in Existing Fragment Libraries . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 3
Peter S. Kutchukian , S ung-Sau S o , C hristian Fischer ,
and Chris L. W aller
PART II SIMULATION
6 Protocol for Fragment Hopping . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 7
Kevin B. Teuscher and Haitao J i
7 S ite Identification by Ligand Competitive Saturation (SILCS)
Simulations for Fragment-Based Drug Design. . . . . . . . . . . . . . . . . . . . . . . . . 75
Christina E. F aller , E. Prabhu R aman , Alexander D . MacKerell, Jr. ,
and Olgun Guvench
8 A Computational Fragment-Based De Novo Design Protocol
Guided by Ligand Efficiency Indices (LEI). . . . . . . . . . . . . . . . . . . . . . . . . . . 89
Álvaro C ortés-Cabrera , Federico Gago , and Antonio M orreale
9 S coring Functions for Fragment-Based Drug Discovery. . . . . . . . . . . . . . . . . . 1 01
Jui-Chih W ang and J ung-Hsin Lin
PART III DESIGN
10 Computational Methods for Fragment-Based Ligand Design:
Growing and Linking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 19
Rachelle J. Bienstock
11 Design Strategies for Computational Fragment-Based Drug Design . . . . . . . . 1 37
Zenon D . Konteatis
vii
viii Contents
12 Protein Binding Site Analysis for Drug Discovery Using a Computational
Fragment-Based Method. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
Jennifer L. L udington
PART IV CASE STUDIES
13 Fragment-Based Design of Kinase Inhibitors: A Practical Guide. . . . . . . . . . . . 157
Jon A . E rickson
14 D esigning a Small Molecule Erythropoietin Mimetic. . . . . . . . . . . . . . . . . . . . 1 85
Frank G uarnieri
15 D esigning an Orally Available Nontoxic p38 Inhibitor
with a Fragment-Based Strategy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
Frank G uarnieri
Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 27
Contributors
RACHELLE J. B IENSTOCK • Independent Researcher and Consultant , C hapel Hill, N C, USA
ÁLVARO C ORTÉS-CABRERA • Unidad de Bioinformática, C entro de Biología Molecular Severo
Ochoa (CSIC-UAM) , M adrid , S pain ; Á rea de Farmacología, Departamento de Ciencias
Biomédicas, U niversidad de Alcalá , Madrid , S pain
JON A . E RICKSON • Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, IN, U SA
CHRISTINA E . FALLER • Department of Pharmaceutical Sciences, College of Pharmacy,
University of New England , P ortland, ME, USA
CHRISTIAN F ISCHER • Discovery Chemistry , Merck Research Laboratories , B oston, M A , U SA
FEDERICO G AGO • Área de Farmacología, Departamento de Ciencias Biomédicas,
Universidad de Alcalá , Madrid, Spain
FRANK GUARNIERI • Department of Physiology & Biophysics, V irginia Commonwealth
University School of Medicine , Richmond, VA , U SA ; P hase III Pharmaceuticals ,
Brooklyn , N Y , U SA
OLGUN GUVENCH • Department of Pharmaceutical Sciences, College of Pharmacy,
University of New England , P ortland, ME, USA
NIU H UANG • Dr. Niu Huang’s Lab, National Institute of Biological Sciences , Beijing, China
HAITAO JI • Department of Chemistry, Center for Cell and Genome Science, U niversity
of Utah , S alt Lake City, U T , USA
RAED S. K HASHAN • Department of Pharmaceutical Sciences, College of Clinical Pharmacy,
King Faisal University , Al-Ahsa, Saudi Arabia ; L aboratory for Molecular Modeling,
Division of Chemical Biology & Medicinal Chemistry, The UNC Eshelman School
of Pharmacy, U niversity of North Carolina at Chapel Hill , C hapel Hill, NC, U SA
ZENON D . KONTEATIS • Agios Pharmaceuticals , C ambridge, M A, U SA
PETER S. K UTCHUKIAN • Merck Research Laboratories , B oston , M A, U SA
JUNG-HSIN LIN • Division of Mechanics, Research Center for Applied Sciences, and Institute
of Biomedical Sciences, A cademia Sinica , Taipei, T aiwan ; S chool of Pharmacy, N ational
Taiwan University , T aipei , T aiwan
JENNIFER L. L UDINGTON • Locus Pharmaceuticals, Inc. , B lue Bell, P A, USA
ALEXANDER D . MACKERELL , JR. • Department of Pharmaceutical Sciences, School of Pharmacy,
University of Maryland , B altimore , M D , USA
ANTONIO MORREALE • Unidad de Bioinformática , C entro de Biología Molecular Severo
Ochoa , M adrid , S pain ; Repsol Technology Center , M adrid , S pain
E. PRABHU RAMAN • Department of Pharmaceutical Sciences, School of Pharmacy,
University of Maryland , B altimore, MD , U SA
SUNG-SAU SO • Computational Chemistry , M erck Research Laboratories, Kenilworth, N J , USA
KEVIN B. T EUSCHER • Department of Chemistry, Center for Cell and Genome Science,
University of Utah , Salt Lake City, UT , U SA
CHRIS L . W ALLER • Scientifi c Modeling Platforms , Merck Research Laboratories, Boston,
MA , USA
JUI-CHIH WANG • Division of Mechanics, Research Center for Applied Sciences , A cademia
Sinica , T aipei, T aiwan
YU Z HOU • Dr. Niu Huang’s Lab, National Institute of Biological Sciences , Beijing, C hina
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