Chapter category: Drug Design
Modeling Structure-Activity Relationships
Adaptive Systems in Drug Design
Edited by: Gisbert SchneiderISBN: 1-58706-059-0
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Chapter authors:
Gisbert Schneider
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Traditionally, the design of novel drugs has essentially been a trial-and-error process despite the tremendous efforts devoted to it by pharmaceutical and academic research groups. It is estimated that only one in 5,000 compounds investigated in preclinical discovery research ever emerges as a clinical lead, and that about one in 10 drug candidates in development ever gets through the costly process of clinical trials. For each drug, the investment may be on the order of $600 million over 15 years from its first synthesis to FDA approval. In 2000, U.S. pharmaceutical companies spent more than $22 billion in research and development, which, after inflation adjustment, represents a four-fold increase from the corresponding figure some 20 years ago. In an attempt to counter these rapidly increasing costs associated with the discovery of new medicines, revolutionary advances in basic science and technology are reshaping the manner in which pharmaceutical research is conducted. For example, the use of DNA microarrays facilitates the identification of novel disease genes and also opens up other interesting opportunities in disease diagnosis, pharmacogenomics and toxicological research (toxicogenomics). The development of combinatorial chemistry and parallel synthesis methods has increased both the quantity and chemical diversity of potential leads against new targets. Our ability to discover useful leads has been greatly enhanced through astonishing advances in high-throughput screening (HTS) technologies. Through miniaturization and robotics, we now have the capacity to screen millions of compounds against therapeutic targets in very short period of time. Central to this new drug discovery paradigm is the rapid explosion of computational techniques that allow us to analyze vast amount of data, prioritize HTS hits and guide lead optimization. The advances and applications of computational methods in drug design are beginning to have a significant impact on the prosperity of the pharmaceutical industry.
Modern approaches to computer-aided molecular design fall into two general categories. The first includes structure-based methods which utilize the three-dimensional structure of the ligand-bound receptor. Many innovative algorithms have been developed and implemented to construct de novo ligands that fit the receptor binding-site in a complementary manner; some of these will be discussed in Chapter 5. The second approach includes ligand-based methods in which the physicochemical or structural properties of ligand molecules are characterized. A classic example of this concept is a quantitative structure-activity relationship (QSAR) model, which grants a theoretical ground for lead optimization.
Additional chapters from this book:
Analysis of Chemical Space
Gisbert Schneider
A main goal of virtual screening is to select activity-enriched sets of molecules — or single molecules exhibiting desired activity—from the space of all synthetically accessible ...
Evolutionary De Novo Design
Gisbert Schneider
"GAs have been shown to be capable of describing extremely complex bahaviour in a range of application domains, including those of molecular recognition and design." (P. Willett)
Prediction of Drug-Like Properties
Gisbert Schneider
Historically, computer-aided molecular design (CAMD) has focused on lead identification and lead optimization, and many innovative strategies have been developed that assist in improving th...
Modeling Structure-Activity Relationships
Gisbert Schneider
Traditionally, the design of novel drugs has essentially been a trial-and-error process despite the tremendous efforts devoted to it by pharmaceutical and academic research groups. It is es...
A Conceptual Framework
Gisbert Schneider
"It is no longer just sufficient to synthesise and test; experiments are played out in silico with prediction, classification, and visualisation being the necessary tools of medicin...
