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What do we know about molecular interactions, and what can they tell us about rational drug design? A medicinal chemist’s guide to molecular interactions¹ summarizes the state of the art in a lengthy but fascinating account. Combining literature data and searches of structural databases, the authors conclude (among other things) that ‘holistic’ models are required to fully understand solvent effects, and that models remain models until experimentally validated. This might seem obvious, but they lament that it has become common practice today to mingle models and reality.

Talking of chemistry and bonds, I’ve always thought it pretty amazing that the cell manages to make DNA without accidentally slipping in a few ribonucleotides. They manage this of course because DNA polymerases manage to selectively ignore ribonucleotides, preventing the incorporation of bases containing that yummily reactive 2’-hydroxyl of the ribose ring. Now, following on from in vitro work, a collaboration working in Sweden and North Carolina has shown that DNA polymerases can indeed be induced to incorporate rNTPs² in vivo. When this happens, it’s not all over for the genome, because an RNAse H2 repair pathway can fix it. Knocking out that pathway results in replicative stress genome instability.

In cancer, genes can be inactivated by aberrant hypermethylation of promoters, and repressive chromatin structure. These epigenetic marks are now shown to be independent of where in the nucleus the DNA actually³ is (or potentially that cancer-induced methylation causes random rearrangement of chromatin, I guess). This implies that, in cancer at least, the local chromatin state/hypermethylation is more important for repression of genes and gene clusters than the localization within the nucleus.

And finally… the Theileria are strange beasts. They parasitize cattle, and are responsible for large economic losses particularly in East and southern Africa. They exist as a mult-nucleate syncitium in the cytoplasm of lymphocytes and monocytes, and induce uncontrolled proliferation in the cells they infect, which causes a cancer-like phenotype that serves as a model of parasite-induced leukemia. But where they get really tricksy is in how they manage to distribute themselves equally at mitosis of these continually dividing cells. These parasites never leave the host cell to infect a new one, but on infection a parasite attaches itself to microtubules emanating from spindle poles, thereby positioning over where host cell chromosomes assemble at mitosis. It then co-opts a host mitotic kinase⁴ to control cell division and ensure its continued infection and proliferation. Very smart.

Evaluated papers

1. Medicinal chemistry 10.1021/jm100112j Open Access
2. The wrong nucleotide 10.1038/nchembio.424
3. Cancer chromatin 10.1158/0008-5472.CAN-10-0765
4. Smart parasites 10.1371/journal.pbio.1000499 Open Access