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Instruments / Technical Area	Publication Details	Published	Actions
I04-Macromolecular Crystallography	Evaluation of 3- and 4-phenoxybenzamides as selective inhibitors of the mono-ADP-ribosyltransferase PARP10 Patricia Korn , Arno Classen , Sudarshan Murthy , Riccardo Guareschi , Mirko M. Maksimainen , Barbara E. Lippok , Albert Galera‐prat , Sven T. Sowa , Catharina Voigt , Giulia Rossetti , Lari Lehtio , Carsten Bolm , Bernhard Lüscher Chemistryopen 384 DOI: 10.1002/open.202100087 Diamond Proposal Number(s): [19951] Open Access Show Abstract ▼ Abstract: Intracellular ADP-ribosyltransferases catalyze mono- and poly-ADP-ribosylation and affect a broad range of biological processes. The mono-ADP-ribosyltransferase PARP10 is involved in signaling and DNA repair. Previous studies identified OUL35 as a selective, cell permeable inhibitor of PARP10. We have further explored the chemical space of OUL35 by synthesizing and investigating structurally related analogs. Key synthetic steps were metal-catalyzed cross-couplings and functional group modifications. We identified 4-(4-cyanophenoxy)benzamide and 3-(4-carbamoylphenoxy)benzamide as PARP10 inhibitors with distinct selectivities. Both compounds were cell permeable and interfered with PARP10 toxicity. Moreover, both revealed some inhibition of PARP2 but not PARP1, unlike clinically used PARP inhibitors, which typically inhibit both enzymes. Using crystallography and molecular modeling the binding of the compounds to different ADP-ribosyltransferases was explored regarding selectivity. Together, these studies define additional compounds that interfere with PARP10 function and thus expand our repertoire of inhibitors to further optimize selectivity and potency.	Jun 2021
I04-Macromolecular Crystallography	Design and synthesis of imidazole and triazole pyrazoles as Mycobacterium tuberculosis CYP121A1 inhibitors Safaa M. Kishk , Kirsty J. Mclean , Sakshi Sood , Darren Smith , Jack W. D. Evans , Mohamed A. Helal , Mohamed S. Gomaa , Ismail Salama , Samia M. Mostafa , Luiz Pedro S. De carvalho , Colin W. Levy , Andrew W. Munro , Claire Simons Chemistryopen 8, 995 - 1011 DOI: 10.1002/open.201900227 Diamond Proposal Number(s): [17773] Open Access Show Abstract ▼ Abstract: The emergence of untreatable drug‐resistant strains of Mycobacterium tuberculosis is a major public health problem worldwide, and the identification of new efficient treatments is urgently needed. Mycobacterium tuberculosis cytochrome P450 CYP121A1 is a promising drug target for the treatment of tuberculosis owing to its essential role in mycobacterial growth. Using a rational approach, which includes molecular modelling studies, three series of azole pyrazole derivatives were designed through two synthetic pathways. The synthesized compounds were biologically evaluated for their inhibitory activity towards M. tuberculosis and their protein binding affinity (KD). Series 3 biarylpyrazole imidazole derivatives were the most effective with the isobutyl (10 f) and tert‐butyl (10 g) compounds displaying optimal activity (MIC 1.562 μg/mL, KD 0.22 μM (10 f) and 4.81 μM (10 g)). The spectroscopic data showed that all the synthesised compounds produced a type II red shift of the heme Soret band indicating either direct binding to heme iron or (where less extensive Soret shifts are observed) putative indirect binding via an interstitial water molecule. Evaluation of biological and physicochemical properties identified the following as requirements for activity: LogP >4, H‐bond acceptors/H‐bond donors 4/0, number of rotatable bonds 5–6, molecular volume >340 Å3, topological polar surface area <40 Å2.	Jul 2019

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