Structural alerts

In several studies of toxicity, no adverse effects were documented in monkeys or humans. Taking into account data showing that lutein was not genotoxic, had no structural alert, did not exhibit tumor-promoting activity, and is a natural component of the body (the eye), the Scientific Steering Committee concluded there was no need for a study of carcinogenicity. 

Explosivity Capacity to liberate heat and gases Structural alerts Heats of formation... 

The major drawback of the ElogD method is that it cannot be applied to acidic compounds ionized at pH 7.4. However, on prachcal grounds, the latter represent a minor fraction of compounds in pharmaceutical libraries and structural alerts could be developed which are used to filter acidic compounds prior to the determination of Elog D in an automated fashion. 

These unwanted functional groups can be easily encoded as SMARTS [37] to be used as structural alerts for HTS compound prioritization or compound acquisition. OpenEye s Filter [38] is an excellent example of such a filtering tool. 

Benigni R, Bossa C, Tcheremenskaia O, Worth A (2009) Development of structural alerts for the in vivo micronucleus assay in rodents. European Commission Report EUR 23844 EN... 

Ashby J. 1985. Fundamental structural alerts to potential carcinogenicity or non-carcinogenicity. Environ Mutagen 7 919-921. 

The dangerous properties of acute toxicity, irritation, corrosivity, sensitisation, repeated-dose toxicity and CMR are evaluated in terms of their potential toxic effects to workers, consumers and man exposed indirectly via the environment, based on the use for each stage in the lifecycle of the substance from which exposure can occur. Risk assessment is also required if there are reasonable grounds for concern for potential hazardous properties, e.g., from positive in vitro mutagenicity tests or structural alerts. The risk assessment involves comparing the estimated occupational or consumer exposure levels with the exposure levels at which no adverse effects are anticipated. This may be a quantitative risk assessment, based on the ratio between the two values, or a qualitative evaluation. The principles of human health risk assessment are covered in detail by Illing (a.30) and more briefly in Chapter 7 of (73). 

There are no formal criteria to identify structural alerts for toxicity in general, for a specific endpoint or for read-across to closely related substances. However, for substances where no data for one or more endpoints are available, the assessment at a screening level can be performed using data obtained from closely analogous substance(s) to indicate a potential for toxicity, e.g., if a closely related substance has a potential for inducing a specific toxic effect, the substance for which no data on this specific toxic effect are available may reasonably be expected to exhibit a similar potential for inducing this specific toxic effect. In the case of such knowledge, it should be considered whether these data are adequate for a hazard assessment. 

The chemical stmcture of a substance may contain structural alerts for certain endpoints, based on clear evidence for such endpoints of strucmral analogues. 

Useful data for the hazard assessment may also be obtained from studies on toxicokinetics (including metabolism), in vitro studies on macromolecule binding, from knowledge of the reactivity and electrophilicity of a substance, and from the presence or absence of structural alerts for genotoxicity. 

Reactivity of the substance, e.g., rate of hydrolysis, electrophilicity, presence or absence of structural alerts. 

When structurally alerting compounds (e.g. those possessing alkylating electrophilic centres) have given negative results in the standard battery. 

Key Words Prioritization compound quality structural diversity consensus scoring regularization molecular complexity structural alerts biological promiscuity. 

Figure 16 shows that compounds with structural alerts, substructural features that are generally not wanted in drug candidates but may be acceptable in lead compounds, are pushed back into the fifth and sixth lists. 

Fig. 16. Distribution of structural alerts grouped by priority list.

Figure 15.1 Compilation of structural alerts/toxicophores known to undergo bioactivation and examples of hepatotoxic drugs containing the structural alerts.

Especially for sensitization, structural alerts may be important for in silica evaluation (see Section 18.2.1)... 

Calculate the molecular weight and structural alerts (substructures containing undesirable or reactive functionalities) for 5,832 amines (rrrNote 1). 

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