Bond stability of the “undesirable” heteroatom–heteroatom molecular moieties for high-throughput screening libraries

Compounds containing heteroatom–heteroatom bonds are regarded as “undesirable” in drug discovery projects possibly due to their inherent fragility, i.e., low bond dissociation energies (BDEs). However, many marketed drugs contain these molecular moieties and it can therefore be argued that the drugs have stronger bonds than generic organic compounds. In this study heteroatom–heteroatom BDEs for marketed drugs and non-drugs are calculated using the Density Functional Theory (DFT). The compounds containing heteroatom–heteroatom moieties were separated into six groups, i.e., N–N, N–O, N–S, O–S, O–O and S–S. No statistical difference was found for the N–N, N–O and O–S groups between the drugs and non-drugs. A statistical significant difference of ∼10 kcal mol−1was observed for the N–S moiety however all of the compounds investigated were sulphonamides. No drugs with the O–O moiety were found and the generic organic compounds had very low average BDE (26.6 ± 4.0 kcal mol−1) explaining their absence. For the S–S scaffold not enough data was available to make a meaningful statistical analysis. The results indicate that low BDE is not the main factor why heteroatom–heteroatom compounds are excluded from drug discovery projects. A more plausible explanation is their electron rich nature which leaves them susceptible to electrophilic attack in biochemical assays, which often leads to false positives and renders this class of compounds “undesirable” in screening collections. However, by omitting these compounds valuable areas in chemical space can be overlooked.

The heteroatom–heteroatom bond moieties deemed to be “undesirable” in drug discovery/development.Figure optionsDownload as PowerPoint slideHighlights
► BDEs of heteroatom–heteroatom “undesirable” moieties were calculated.
► No difference was found between drugs and non-drugs.
► Therefore bond fragility not the cause of “undesirability”.
► The electron rich nature of heteroatom–heteroatom bonds gives rise to false positives.