Toxicity drug discovery programs

A major problem in aU drug discovery programs is to discover compounds with good pharmacokinetics. Although it is possible to examine the metabolism of the drug in animals, it has often been difficult to predict what would happen in man. The obvious implications of drug metabolism are an effect on half-life in vivo and the production of toxic metabolic products. 

As a result of the screening process used during drug discovery, active substances will be identified. Of these active substances, the compound that best fits the desired characteristics profile (pharmacological activity, lack of early toxicity, patentability, etc) will be declared a lead compound. Development activities will then begin to shift from a broad discovery program to a more focused development program centred around the lead compound. 

A QSAR seeks to relate quantitative properties (descriptors) of a compound with other properties such as drug-like activity or toxicity. The essential assumption of QSAR is that quantities that can be conveniently measured or calculated for a compound can be used to accurately predict another property of interest (e.g., antibacterial activity) in a nontrivial way. QSAR has become an integral part of screening programs in pharmaceutical drug-discovery pipelines of small compounds and more recently in toxicological studies (69). However, the use of QSAR modeling applied to the search for antimicrobial peptides is relatively recent. Advances in this area are reviewed in brief here. 

If a chemical hit (series) identified from screening has clear potential chemical liability that would limit the ability to develop the compound and related analogs then it is unlikely to be selected with high priority to move into the hit-to-lead phase. This is less of an issue for probe development, for example oral bioavailability is rarely a criteria for a chemical probe (even if desirable), similarly potential in vivo toxicity liabilities of a hit are not of concern for initiating a probe development program. While medicinal chemists and pharmacologists on a drug discovery or probe discovery team... 

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