This book is intended to provide an integrated and comprehensive overview of modern approaches to multi-target drug discovery (MTDD) and the state of our knowledge in the over-arching field of polypharmacology. Given the intense current interest in this field, the editors hope that the book will be of significant interest to medicinal and computational chemists in the commercial sector and in academia, as well as the wider drug discovery community. Many readers will already be aware of the serendipitous nature of the discovery of many existing multi-target drugs. In this book the editors focus on the rational and practical execution of MTDD. The chapters are written by widely recognized experts and opinion leaders in the field. The first challenge of MTDD is to identify biologically validated combinations of targets relevant to a disease state. However it is equally important that these disease relevant combinations are chemically tractable from a medicinal chemistry perspective. The book thus follows a natural thread from target identification and validation, through lead generation and lead optimisation, and finally to clinical development. A key feature of the book is a collection of seminal case studies chosen to illustrate the challenges and opportunities of MTDD. These include compounds at various stages of development from pre-clinical to marketed drugs.
Inhaltsverzeichnis
Preface; Forewords; Simple drugs do not cure complex diseases - the need for multi-targeted drugs; Clinical Need and Rationale for Multi-Target Drugs in Psychiatry; Drug molecules and biology: network and systems aspects; Chemoinformatic approaches to target identification; In vitro Panel Screening - Biological Fingerprinting; Phenotypic and in vivo Screening; Lead Discovery and Drug Repurposing; Target/s identification approaches - experimental biological approaches; Historical strategies for lead generation; In silico Lead Generation Approaches in Multi-Target Drug Discovery; The challenges of multi-target lead optimization; Combination agents versus multi-targeted agents - pros and cons; CASE STUDIES: The Discovery of Lapatinib; Identification and optimization of dual PI3K/mTOR inhibitors; Discovery of HDAC-inhibiting multi-target inhibitors; Targeting protein-protein interactions; dual inhibitors of Bcl-2 and Bcl-xL; Discovery of the anti-psychotic drug, Ziprasidone; The Rational Design of Triple Reuptake Inhibitors for the Treatment of Depression; Discovery of multi-target agents for neurological diseases via ligand design; Designing Drugs with Dual Activity: Novel Dual Angiotensin II and Endothelin Receptor Antagonists; Case study 10: Ethyl Urea Inhibitors of the Bacterial Type II Topoisomerases DNA Gyrase (GyrB) and Topoisomerase IV (ParE); Epilogue; Index
