Here we present an evaluation of the binding affinity prediction accuracy of the free energy calculation method FEP+ on internal active drug discovery projects and on a large new public benchmark set. File list (3) download file view on ChemRxiv manuscript.pdf (4.23 MiB) download file view on ChemRxiv supplementary.pdf (0.92 MiB) download file view on ChemRxiv tables.zip (5.99 KiB)
Here we present an evaluation of the binding affinity prediction accuracy of the free energy calculation method FEP+ on internal active drug discovery projects and on a large new public benchmark set.<br>
The formamidopyrimidine (FapydGua) lesion, derived from the nucleobase guanine, is a major DNA lesion involved in mutagenesis and carcinogenesis. To date, the chemical information available about this main lesion is very limited. Herein, we describe a synthesis and a detailed characterization of the acetyl-protected monomer of the FapydGua lesion. Stability studies in DMSO and in water/acetonitrile show that the N-glycosidic bond, previously thought to be highly labile, is much more stable than anticipated. Decomposition of the FapydGua lesion proceeds with half-life times of 37.8 h for the beta-anomer and 65.2 h for the alpha-anomer in water/acetonitrile. The relaxation time for the anomerization reaction was determined to tau = 6.5 h at room temperature. Most important, it was found that the formamido group, which is critical for the lesion recognition process by repair enzymes, is fixed in the cis-conformation in apolar solvents such as chloroform. This conformation enables the formation of a hydrogen bond between the carbonyl oxygen of the formamide and the NH of the N-glycosidic bond within the framework of a seven-membered ring system. This has consequences for the recognition of the lesion by repair enzymes (hOGG1 and Fpg protein). These enzymes were so far believed to recognize the carbonyl group of the FapydGua lesion. Our investigations show that this carbonyl group is not readily accessible because it is almost buried in the dominating cis-conformation. In agreement with the recent X-ray structure of hOGG1 in complex with 8-oxo-7,8-dihydroguanine-containing DNA, we can conclude that repair enzymes can contact both lesions only via the N(7)-H group, which is a hydrogen-bond acceptor in guanine.
Remote reductive repair of thymine dimers in a DNA duplex by transfer of excess electrons over a distance of up to roughly 24 Å (n=7) has been attributed to thermally activated hopping (see scheme). Possible consequences for humans: the harmful effect of UV irradiation responsible for the development of skin cancer could potentially be reduced by compounds that bind to DNA and trigger long‐range electron transport.
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