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Occasionally a med-chemist will remark that they think a particular molecule has a 'reactive centre' and so should be de-prioritised (in the context of hit- and drug- discovery).

Leaving aside known metabolic enzymes, which will catalyse certain reactions, speeding them up beyond what you'd see passively, is there some metric available to highlight 'reactive centres'? Perhaps Fukui indices are suitable here - but, as noted on the XTB website:

As the Fukui indexes depend on occupation numbers and population analysis (see Properties), they are sensitive toward basis set changes. Therefore Fukui indexes should not be recognized as absolute numbers but as relative parameters in the same system.

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    $\begingroup$ The note on the xtb website is probably intended in the limited context of xtb itself, which uses a basis set of limited size since the tight-binding method also has inherent error. $\endgroup$ Nov 2, 2022 at 11:18
  • $\begingroup$ thanks @SusiLehtola - by 'system' do you think they mean molecular system (i.e. don't compare across different molecules) or basis set (i.e. don't compare across different basis sets)? $\endgroup$
    – lewiso1
    Nov 2, 2022 at 19:48
  • $\begingroup$ I guess Fukui indices are suitable to find out nucleophilic or electrophilic centres. Although reactivity really depends on the enzymes available in the body. Specific enzymes look for specific functional groups so I guess it is hard to have a unified metric. Also, some people have done research on identifying toxicity form structures, and there are some substructures which tend to indicate toxicity at specific point (e.g. mitchondrial toxicity) $\endgroup$
    – S R Maiti
    Nov 3, 2022 at 11:15
  • $\begingroup$ I guess Fukui indices are suitable to find out nucleophilic or electrophilic centres. Although reactivity really depends on the enzymes available in the body. Specific enzymes look for specific functional groups so I guess it is hard to have a unified metric. Also, some people have done research on identifying toxicity form structures, and there are some substructures which tend to indicate toxicity at specific point (e.g. mitchondrial toxicity) $\endgroup$
    – S R Maiti
    Nov 3, 2022 at 11:16
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    $\begingroup$ obvious to you maybe :) it sounds like you know a lot about the topic, if you could submit an answer that would be really helpful! $\endgroup$
    – lewiso1
    Nov 3, 2022 at 23:49

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