ABSTRACT
H istorically, com puter-aided m olecular design (C A M D ) has focused on lead identification and lead optimization, and many innovative strategies have been
developed that assist in improving the binding affinities o f drug candidates to spe-
cific receptors. One such method, QSAR, has been discussed in the previous Chapter. In this Chapter, we will discuss the emerging concept o f “drug-likeness” , as well as the computational
modeling o f a set o f physicochemical and biological properties that play an important role in
the transformation o f 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inhibitor and a bioavailable drug.1 Far too often, promising candidates are abandoned during clinical trials-or worse, withdrawn after market launch in the medico-economic phase-for a variety o f reasons, including low bioavailability, high toxicity, poor pharmacokinetics, or drug-drug interactions. In addition, the advent o f 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 o f 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 o f drug action. The study of pharmacokinetics refers to the journey o f the drug from its point o f entry to the site o f action. Broadly speaking, this process can be defined by the following phases: absorption, distribution, metabolism, and excretion (ADM E). The first hurdle for an orally administrated drug is ad-
equate 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 o f 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 subse-
quently 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.
