Katrina S. Madden

Complement-based drug discovery is undergoing a renaissance, empowered by new advances in structural biology, complement biology and drug development. Certain components of the complement pathway, ...

The androgen receptor (AR) is an important drug target in prostate cancer and a driver of castration-resistant prostate cancer (CRPC). A significant challenge in designing effective drugs lies in targeting constitutively active AR variants and, most importantly, nearly all AR variants lacking the ligand-binding domain (LBD). Recent findings show that an AR’s constitutive activity may occur in the presence of somatic DNA mutations within non-coding regions, but the role of these mutations remains elusive. The discovery of new drugs targeting CRPC is hampered by the limited molecular understanding of how AR binds mutated DNA sequences, frequently observed in prostate cancer, and how mutations within the protein and DNA regulate AR-DNA interactions. Using atomistic molecular dynamics (MD) simulations and quantum mechanical calculations, we focused our efforts on (i) rationalising the role of several activating DBD mutations linked to prostate cancer, and (ii) DBD interactions in the presence of abasic DNA lesions, which frequently occur in CRPC. Our results elucidate the role of mutations within DBD through their modulation of the intrinsic dynamics of the DBD-DNA ternary complex. Furthermore, our results indicate that the DNA apurinic lesions occurring in the androgen-responsive element (ARE) enhance direct AR-DNA interactions and stabilise the DBD homodimerisation interface. Moreover, our results strongly suggest that those abasic lesions may form reversible covalent crosslinks between DNA and lysine residues of an AR via a Schiff base. In addition to providing an atomistic model explaining how protein mutations within the AR DNA-binding domain affect AR dimerisation and AR-DNA interactions, our findings provide insight into how somatic mutations occurring in DNA non-coding regions may activate ARs. These mutations are frequently observed in prostate cancer and may contribute to disease progression by enhancing direct AR-DNA interactions.

High quality chemical probes and chemistry-based target deconvolution techniques will be crucial to the advancement of phenotypic drug discovery, providing new hope for treatment of diseases with highly complex biology.

Barriers to the ready adoption of biocatalysis into asymmetric synthesis for early stage medicinal chemistry are addressed, using ketone reduction by alcohol dehydrogenase as a model reaction. An efficient substrate screening approach is used to show the wide substrate scope of commercial alcohol dehydrogenase enzymes, with a high tolerance to chemical groups employed in drug discovery (heterocycle, trifluoromethyl and nitrile/nitro groups) observed. We use our screening data to build a preliminary predictive pharmacophore-based screening tool using Forge software, with a precision of 0.67/1, demonstrating the potential for developing substrate screening tools for commercially available enzymes without publically available structures. We hope that this work, combined with our simple protocols for scaleable H2-driven biocatalytic ketone reduction, will facilitate a culture shift towards adopting biocatalysis alongside traditional chemical catalytic methods.

Two truncated analogues of the polyenyl photoprotective xanthomonadin pigments have been synthesised utilising an iterative Heck–Mizoroki (HM)/iododeboronation cross coupling approach and investigated as models of the natural product photoprotective agents in bacteria. Despite the instability of these types of compounds, both analogues proved to be sufficiently stable to allow isolation, spectroscopic analysis and biological studies of their photoprotective behaviour which showed that despite their shorter polyene chain length, they retained the ability to protect bacteria from photochemical damage; i.e. incorporation of one compound into E. coli provided photoprotective activity against singlet oxygen analogous to the natural photoprotective mechanisms employed by Xanthomonas bacteria, answering key questions about what minimal functionality is required to impart photoprotection, potentially leading to new classes of photoprotective and antioxidants compounds.

A number of aryl building blocks for the synthesis of two xanthomonadin natural product pigments, as well as a related analogue, were accessed using a divergent hydroboration/bromoboration approach from a key alkynyl intermediate. A new approach towards substitution patterns around the ring was adopted following the isolation of an unexpected regioisomer from the bromination reaction. Potential coupling reactions onto these building blocks were explored, with a successful Sonogashira coupling performed on the key alkynyl intermediate, and with the key debrominated styrenyl boronate ester intermediate functionalised both by preliminary Suzuki–Miyaura coupling and by iododeboronation/Heck–Mizoroki coupling. Coupling reactions with brominated styrenyl intermediates proved much more challenging due to the instability of the intermediates to cross‐coupling, but some studies have shown promise.

Vinyliodide reacts chemoselectively under Heck–Mizoroki conditions with terminal alkenes to give diene products, including vinyl boronate esters, and the resulting dienylboronate undergoes Suzuki–Miyaura coupling with aryl, heteroaryl and alkenyl halides to access dienes and trienes.