Chapter category: Drug Design
Prediction of Drug-Like Properties
Adaptive Systems in Drug Design
Edited by: Gisbert SchneiderISBN: 1-58706-059-0
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Chapter authors:
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 the binding affinities of drug candidates to specific receptors. One such method, QSAR, has been discussed in the previous Chapter. In this Chapter, we will discuss the emerging concept of "drug-likeness", as well as the computational modeling of a set of physicochemical and biological properties that play an important role in the transformation of a clinical lead to a marketed drug.
Although high potency is an important factor in pharmacological design, one must also recognize the huge gulf between a tightly bound inhibitor and a bioavailable drug.1 Far too often, promising candidates are abandoned during clinical trials—or worse, withdrawn after market launch in the medico-economic phase—for a variety of reasons, including low bioavailability, high toxicity, poor pharmacokinetics, or drug-drug interactions. In addition, the advent of parallel synthesis methods and high throughput screening has placed increasing stress on the technology that has traditionally been used to assess potential drug candidates in non-clinical development. Due to the limited time and resources available to conduct formal in vivo studies, typically only tens of candidates will be screened. Thus, prioritization by computational means prior to experiment is important in order to ensure that valuable resources are apportioned to the most promising candidates.
Drug molecules generally act on specific targets at the cellular level, and exert therapeutic action upon binding to receptors that subsequently modify the cellular machinery. Before a drug molecule exerts its pharmaceutical (pharmacodynamic) effect on the body via interaction with its target, it must travel through the body to reach the site of drug action. The study of pharmacokinetics refers to the journey of the drug from its point of entry to the site of action. Broadly speaking, this process can be defined by the following phases: absorption, distribution, metabolism, and excretion (ADME). The first hurdle for an orally administrated drug is adequate absorption from the gut wall into the blood circulatory system. Upon absorption, it will be transported to the liver, where it is liable to modification by a panel of hepatic microsomal enzymes; some molecules may be metabolized and some may be excreted via the bile. If a drug molecule survives this first pass metabolism, it will enter arterial circulation, and is subsequently distributed to the body, including the target tissue. Once the drug has triggered the desirable therapeutic response, it should be steadily eliminated from the body; otherwise bioaccumulation may become a concern. In addition, a drug must not cause any serious toxic side effects, including, but not limited to interference with the actions of any other drugs the patient may be taking. Such interference is normally caused by enzyme induction, a process in which one drug stimulates an enzyme, thereby causing a change in the metabolism of a second drug.
Additional chapters from this book:
Analysis of Chemical Space
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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
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"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
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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 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...
