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Medicinal chemistry in review: Overcoming PXR liability

By Nick Martin (Associate Principal Scientist, Chemistry) and Andrew Ratcliffe (Associate Director, Chemistry)

In this latest edition of our blog series, we have focussed on a recent publication by Ramanjulu et al.1

There are many challenges to balance in a successful drug discovery project, one of the most notable being compound metabolism. The publication exemplifies a great use of crystallography and modelling to navigate induced CYP expression and therefore rapid metabolism of their calcium sensing receptor antagonist.

The group found that their compound was a strong activator of pregnane X receptor which regulates the expression of many key proteins implicit in all stages of metabolism including CYP450 enzymes. Like the CYP family, PXR has a non-distinct active site in order to bind a wide range of foreign materials. Pharmacophore models do exist and reducing LogP is of course a robust method for reducing off target effects and metabolism, but few techniques are more informative than X-ray crystallography if a structure can be successfully obtained, which was the case here. A binding mode was deduced, and by introducing a clash with the protein in the form of a rigid pyridine, the metabolic liability was largely alleviated.

In this instance, crystallography supported the binding mode identified by molecular modelling meaning that a computational solution would have proven equally valuable should this work have been conducted without the resource that a company like GSK is able to wield.

Domainex is well equipped in both computational chemistry as well as X-ray crystallography and has extensive experience of all stages of drug discovery including finding solutions to challenging problems like the one described above. If you would like to know more, please don’t hesitate to contact us.

We hope you’ve found this interesting, if so look out for our next medicinal chemistry review which will be available on our website soon.

  1. Overcoming the Pregnane X Receptor Liability: Rational Design to Eliminate PXR-Mediated CYP Induction. Joshi M. Ramanjulu, Shawn P. Williams, Ami S. Lakdawala, Michael P. DeMartino, Yunfeng Lan and Robert W. Marquis. ACS Med. Chem. Lett. 2021, 12, 9, 1396–1404

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