DRUG DISCOVERY AND DEVELOPMENT – PRESENT AND FUTURE Edited by Izet M. Kapetanovic           Drug Discovery and Development – Present and Future Edited by Izet M. Kapetanovic Published by InTech Janeza Trdine 9, 51000 Rijeka, Croatia Copyright © 2011 InTech All chapters are Open Access distributed under the Creative Commons Attribution 3.0 license, which allows users to download, copy and build upon published articles even for commercial purposes, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. After this work has been published by InTech, authors have the right to republish it, in whole or part, in any publication of which they are the author, and to make other personal use of the work. Any republication, referencing or personal use of the work must explicitly identify the original source. As for readers, this license allows users to download, copy and build upon published chapters even for commercial purposes, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. Notice Statements and opinions expressed in the chapters are these of the individual contributors and not necessarily those of the editors or publisher. No responsibility is accepted for the accuracy of information contained in the published chapters. The publisher assumes no responsibility for any damage or injury to persons or property arising out of the use of any materials, instructions, methods or ideas contained in the book. Publishing Process Manager Ivana Zec Technical Editor Teodora Smiljanic Cover Designer InTech Design Team Image Copyright Olga Miltsova, 2011. Used under license from Shutterstock.com First published December, 2011 Printed in Croatia A free online edition of this book is available at www.intechopen.com Additional hard copies can be obtained from orders@intechweb.org Drug Discovery and Development – Present and Future, Edited by Izet M. Kapetanovic p. cm. 978-953-307-615-7 free online editions of InTech Books and Journals can be found at www.intechopen.com   Contents  Preface IX Introductory Overview of Current Drug Discovery and Chapter Development with an Eye Towards the Future 1 Izet M. Kapetanovic Part 1 Current Status and Future Directions 7 Chapter 1 Drug Discovery and Ayurveda: Win-Win Relationship Between Contemporary and Ancient Sciences 9 Bhushan Patwardhan and Kapil Khambholja Chapter 2 Evolutionary Biology and Drug Development 25 Pierre M. Durand and Theresa L. Coetzer Chapter 3 Novel Oncology Drug Development Strategies in the Era of Personalised Medicine 43 C.R. Lemech, R.S. Kristeleit and H.T. Arkenau Chapter 4 Drug Discovery into the 21 st Century 69 Klaus Pors Part 2 Models 97 Chapter 5 Genetically Engineered Mouse Models in Preclinical Anti-Cancer Drug Development 99 Sergio Y. Alcoser and Melinda G. Hollingshead Chapter 6 Genetic Pharmacotherapy 125 Celia Gellman, Susana Mingote, Yvonne Wang, Inna Gaisler-Salomon and Stephen Rayport Chapter 7 Critical Human Hepatocyte-Based In Vitro Assays for the Evaluation of Adverse Drug Effects 151 Albert P. Li VI Contents Chapter 8 The Use of In Vitro 3D Cell Models in Drug Development for Respiratory Diseases 169 Song Huang, Ludovic Wiszniewski and Samuel Constant Part 3 Tools, Methods, and Biomarkers 191 Chapter 9 Chemical Biology: What is Its Role in Drug Discovery? 193 Lisa Pirrie and Nicholas J. Westwood Chapter 10 Towards Understanding Drugs on the Molecular Level to Design Drugs of Desired Profiles 231 Jolanta Natalia Latosińska and Magdalena Latosińska Chapter 11 De-Risking Drug Discovery Programmes Early with ADMET 275 Katya Tsaioun and Steven A. Kates Chapter 12 Novel Approach to High Throughput Screening for Activators of Transcription Factors 295 Natalya Smirnova, Dmitry Hushpulian, Rajiv Ratan and Irina Gazaryan Chapter 13 Assessment of Cell Cycle Inhibitors by Flow Cytometry 323 Paolo Cappella and Jürgen Moll Chapter 14 Image-Based High-Content Screening in Drug Discovery 339 Marjo Götte and Daniela Gabriel Chapter 15 Recent Advances in Biotherapeutics Drug Discovery and Development 363 Xiaotian Zhong, Peter Neumann, Michael Corbo and Evan Loh Chapter 16 Drug Discovery by Aptamers in Protozoan Infectious Diseases 379 Carsten Wrenger and Henning Ulrich Chapter 17 Streamlining ICH Q6B Analytical Testing of Biotherapeutics 391 Elizabeth Higgins, Elisabeth Kast and Amy Lachapelle Chapter 18 Biomarkers in Drug Development: A Useful Tool but Discrepant Results May Have a Major Impact 401 Abdel-Baset Halim Contents VII Part 4 Drug Delivery 425 Chapter 19 Nanotechnology Based Targeted Drug Delivery: Current Status and Future Prospects for Drug Development 427 Sadhna Sharma and Amandeep Singh Chapter 20 Silver Nanoparticles – Universal Multifunctional Nanoparticles for Bio Sensing, Imaging for Diagnostics and Targeted Drug Delivery for Therapeutic Applications 463 Anitha Sironmani and Kiruba Daniel Chapter 21 Mesenchymal Stem Cells as Vehicles for Targeted Therapies 489 Gabriele Putz Todd, Michelle A LeRoux and Alla Danilkovitch-Miagkova  Preface  Drug discovery and development process aims to make available medications that are safe and effective in improving the length and quality of life and relieving pain and suffering. However, the process is very complex, time consuming, and resource intensive, requiring multi-disciplinary expertise and innovative approaches. Recent estimates suggest that it takes up to 13.5 years and 1.8 billion U.S. dollars to bring a new drug to the market. There is a growing urgency to identify and develop more effective, efficient, and expedient ways to bring safe and effective products to the market. The drug discovery and developmental process relies on utilizing relevant and robust tools, methods, and models that are predictive of clinical effects in terms of diagnosis, prevention, therapy, and prognosis. There is a growing emphasis on translational research, a bidirectional bench to the bedside approach. The all-important predictivity depends on having robust, relevant, validated and qualified biomarkers for physiological and pathological effects of interest. The first section, Introduction, presents an overview of the principles, approaches, processes, and status of drug discovery today with an eye towards the future. The second section, Current Status and Future Directions, presents a broad picture of the current, emerging, and evolving state of the drug discovery and development. It discusses topics such as chemical genetics, combination of ancient traditional, conventional and evolving systems, biology approaches, role of evolutionary biology, personalized medicine, and interaction. Other topics, such as collaboration between academia, government, and a private sector, and a practical overview of drug development from a big pharma perspective are also explored. Section 3, Models, deals with the existing and emerging models for evaluating efficacy and safety. While model systems provide useful information and approximation to human pathophysiology and pharmacology, it is important to keep in mind that these are only models. They may only be applicable to addressing specific questions, and care must be exercised in their extrapolations. As discussed in Section 4, Tools, Methods and Biomarkers, having and utilizing the right tools is critical during the drug discovery and development process. Biomarkers represent physiological, biochemical, or pathophysiological parameters or sentinels X Preface which are intended to detect or monitor diseases, or the health status of an organism. The aim is to decrease probability of failure, decrease drug development time, and improve resource utilization. Also, biomarkers can provide information that is not readily available otherwise, such as that due to a lack of acceptably invasive procedures or unrealistic time frames. Biomarkers can be used as indices of efficacy, toxicity and for selection of appropriate patient populations. However, there are many caveats and few validated biomarkers. Some of the issues include inter-laboratory variation, lack of adequate sensitivity, specificity and predictability, or adequate knowledge if the biomarkers are within a causative or only a correlative pathway. The final section 5, Drug Delivery, discusses development of appropriate formulations for drug delivery to achieve reasonable bioavailability, access to a target site, desirable pharmacokinetic profile, and a practical dosing regimen. Many drug candidates due to their physicochemical properties suffer from a poor solubility and/or poor permeability. Consequently, the Biopharmaceutics Classification System (BCS) was developed to predict intestinal drug absorption, identify strategies, and improve the efficiency of drug development. Perhaps the most rapidly growing area in drug delivery involves nanotechnology and use of nanoparticles. Nanoparticles range in size between 1 and 100 nm. and have shown usefulness in enhancing bioavailability, providing sustained drug release, and enabling targeted delivery to specific sites in the body. These effects can help improve efficacy and decrease toxicity of drugs. Furthermore, specific forms of nanoparticles, in addition to serving as drug delivery vehicles, can also serve as imaging agents, biosensors, and diagnostic agents. Another new approach involves the use of mesenchymal stem cells for targeted delivery of drugs and nanoparticles to tumors and sites of inflammation. It is our hope that the readers find the book informative and that it stimulates new and innovative ideas to apply to drug discovery and development of the future.  Izet M. Kapetanovic Division of Cancer Prevention, National Cancer Institute, Bethesda, USA [...]... e.com/nbt/journal/v28/n5/index.html ) Advances in hardware and software computational power and sophistication are fueling the rapidly growing reliance on computers and computational modeling in an attempt to 4 Drug Discovery and Development – Present and Future improve the efficiency and effectiveness in the drug discovery and development process [9] It’s not uncommon to hear statements at drug development conferences that computational... Drug rediscovery” would help differentiate process of discovering a drug from totally new chemical entity from the process of understanding a drug which is not totally new to mankind Another extension of Drug rediscovery from ayurvedic drugs can be done for benefit of contemporary science of medicine and that would be “stage 2 drug discovery based on 16 Drug Discovery and Development – Present and. .. Computer-aided drug discovery and development (CADDD): in silico-chemico-biological approach Chem Biol Interact 171: 165-76 [10] Koening J (2011) Does process excellence handcuff drug development? Drug Discov Today 16: 377-381 6 Drug Discovery and Development – Present and Future [11] Kola I (2008) The State of Innovation in Drug Development Clin Pharmacol Ther 83: 227-230 [12] Kola I, Landis J (2004) Can the... Unmada Drug Discovery and Ayurveda: Win-Win Relationship Between Contemporary and Ancient Sciences 15 2.6 Safety pharmacology and drug interaction studies as part of drug discovery based on ayurvedic drugs In contemporary Drug discovery programs safety has prime importance and any molecule must have a favorable risk benefit ratio to be considered and approved as drug Even though ayurvedic drugs and/ or... Aspects of Safety Pharmacology and Drug Interaction Evidencebased Complementary and Alternative Medicine Vol.2011,No., 24 Drug Discovery and Development – Present and Future Sharma H , Chandola HM (2011) Prameha in Ayurveda: Correlation with Obesity, Metabolic Syndrome, and Diabetes Mellitus Part 1–Etiology, Classification, and Pathogenesis The Journal of Alternative and Complementary Medicine Vol.17,No.,... Ayurvedic basis, rather than herbal concoctions Understanding the ayurvedic basis of any 12 Drug Discovery and Development – Present and Future combination of herbs and its use in different condition requires knowledge of ayurvedic fundamentals and its correlation with contemporary concepts Table 1 represent some examples of current evidence for ayurvedic drugs and their untapped potential yet to be established... the key term Drug Rediscovery” is being 10 Drug Discovery and Development – Present and Future presented for the first time with a scientific perspective The later part of the chapter also covers futuristic discussion where possibilities of linking Ayurveda with drug discovery process are described We have tried to lay down conceptual framework for win-win relationship between ancient and contemporary... Ayurvedic plants and impact on therapy and drug discovery 2 Contemporary drug discovery / development research on Ayurvedic concepts and medicines As discussed above Ayurvedic concepts differ significantly when it comes to diagnosis, use of drugs or even treatment pedagogy It is well-known that Ayurveda tries to heal or cure Drug Discovery and Ayurveda: Win-Win Relationship Between Contemporary and Ancient... industry reduce attrition rates? Nat Rev Drug Discov 3: 711-5 [13] Kumar N, Hendriks BS, Janes KA, de Graaf D, Lauffenburger DA (2006) Applying computational modeling to drug discovery and development Drug Discovery Today 11: 806-811 [14] Lowe JA, Jones P, Wilson DM (2010) Network biology as a new approach to drug discovery Current Opinion in Drug Discovery and Development 13: 524-526 [15] Mostrag-Szlichtyng... opinion from affiliating company or organisation 22 Drug Discovery and Development – Present and Future Benefits for Ayurveda Benefits in Chemistry domain - Benefits in Process domain - - - Benefits in Life science domain - - - Benefits for drug discovery / health care sciences Understanding of chemistry behind success of ayurvedic herbs Better understanding of chemical transformation during traditional . DRUG DISCOVERY AND DEVELOPMENT – PRESENT AND FUTURE Edited by Izet M. Kapetanovic           Drug Discovery and Development – Present and Future Edited by Izet. excellence handcuff drug development? Drug Discov Today 16: 377-381 Drug Discovery and Development – Present and Future 6 [11] Kola I (2008) The State of Innovation in Drug Development. . of Current Drug Discovery and Chapter Development with an Eye Towards the Future 1 Izet M. Kapetanovic Part 1 Current Status and Future Directions 7 Chapter 1 Drug Discovery and Ayurveda: