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Structure-Guided Drug Design: Rediscovering the Importance of Drug Structure for Drug Discovery
Drug and Market Development Publishing, Nov 2004, Pages: 500
CHAPTER 1: EXECUTIVE SUMMARY
- Why Structure-Guided Drug Design?
Current Status of the Pharmaceutical Industry
The pharma industry is in a bad way. There are three major reasons for this self-inflicted malaise:
- a total preoccupation with the next blockbuster at the expense of other projects,
- an obsession with technological innovation leading to an “arms-race,” and
- an unsustainable strategy for improving corporate status by buying up the competition.
These are fundamental problems that cannot be resolved by new concepts of drug design. But the rediscovery of the importance of structure, especially in molecular interactions, can be a conceptual focus for restructuring the pharma industry for a new period of sustained growth. Structure-guided drug design is a guide to the rediscovery of the importance of structure, for the whole of the drug discovery pipeline. It is not a report on how drug discovery used to be done in the past, but how it will be done in the future.
Exhibit 1.1 Structure-guided drug design is the modern exploitation of technology-driven drug discovery and computer-driven drug design
(Shown in Full Report)
Structure-guided drug design is the modern manifestation of the drug discovery business, reflecting the movement away from serendipity in Drug Discovery toward rational attempts at Drug Design. Modern drug design is a fusion of the combinatorial, high-throughput, wet, in dustrio conveyer-belt technologies of industry and the dry, in silico correlates of all of these processes, together with the predictive and focusing power of structure-guided, computationally supported decisions. The ultimate goal is to achieve less serendipity and more design by use of high-throughput in both wet and dry discovery channels, with feedback between all components and at all levels.
Classical and New Drug Discovery Paradigms
The establishment of the basic tenets of pharmacotherapeutics as a successful, knowledge-based paradigm, the formalization of the drug discovery pipeline, and the evident utility of the drug design cycle were the crowning achievements of the mature and refined drug discovery paradigm of the 1980s. The elucidation of the molecular properties, which promoted drug uptake, determined the mechanisms of drug metabolism and divulged the basis of activity within the body, producing one success story after the other. This accumulation of knowledge and achievements was primarily in preclinical R&D and these precepts, rightfully, can be designated the classical drug discovery paradigm.
The last century was a period of unmitigated success in the pharmaceutical industry. So what went wrong?
Haphazard investment in new technologies has contributed to an R&D budget hike of nearly 10-fold within the last two decades, during which time the production of new molecular entities (NME) has only doubled. The pouring of money into the newest technological fad has diverted resources away from drug discovery, causing a huge innovation deficit. A new drug now costs between a half and one and a half billion dollars to bring to market.
Will the pharma industry be able to recover from this innovation deficit?
The solution presented in this report is a new paradigm of Drug Discovery by Design, created by implementing Structure-guided drug design throughout the whole of preclinical R&D. It is suggested that assays and technology should be implemented when data is required and not because they generate data per se. When using higher throughput and greater speed, crystal structures and virtual docking, so-called hard data and meta-data, the consequences for discovery or design scenarios must be appreciated and factored in accordingly. Many consequences are elucidated and exemplified for, even with the greatest care in data collection and analysis, inappropriate biochemistry or molecular biology can produce a result that is of questionable worth and utility. It is not possible to provide universal answers, but a microcosm of possibilities is presented which, hopefully, will excite further exploration of drug space.
Viruses and cancer, and hormones and receptors, are recurrent themes throughout this report, documenting the successes and the failures, trying to determine the essential ingredients of a Structure-Guided Drug Designdrug, what creates agonist activity, and how receptors are activated, especially for the biggest receptor family of all.
Receptors are the Major Drug Targets
The largest receptor family of all, both numerically and commercially, consists of the 7-transmembrane receptors (7TMRs), which often are called G protein-coupled receptors (GPCRs). Nearly 70% of drugs target 7TMRs, accounting for sales of over $23.5 billion in 2000.
Only a few of the 7TMRs have an extensive pharmacological repertoire, no 3D structure of the endocrine receptors is known and the problems of establishing a presentation technology for the rapid screening of cell-surface receptors are immense. The great diversity in ligands and receptors has resulted in the prevailing modern view that each ligand-receptor system has unique properties; further confounding the modern approach to drug discovery, with its essentially blind search for random “hits” in combinatorial and conformer space.
Exhibit 1.2 Drug Discovery with 7TMRs will benefit from the decoding of agonist activity and knowledge of the receptor activation mechanism
Given the major importance of the 7TMRs, the structural elucidation of a hormone-occupied endocrine 7TMR represents the Holy Grail for most of the Drug Design community. By concentrating on hormone-receptor systems in structure-guided drug design, issues can be addressed which anticipate this achievement.
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