Development of novel PARP inhibitors based on phenanthridinones using computer-aided drug design

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dc.contributor.authorFang, Yuhua
dc.contributor.examiningcommitteeLakowski, Ted (Pharmacy)en_US
dc.contributor.examiningcommitteeSorensen, John (Chemistry)en_US
dc.contributor.examiningcommitteeRao, Praveen Nekkar (University of Waterloo)en_US
dc.contributor.supervisorTranmer, Geoffrey (Pharmacy)en_US
dc.date.accessioned2022-02-10T21:48:14Z
dc.date.available2022-02-10T21:48:14Z
dc.date.copyright2022-02-09
dc.date.issued2022en_US
dc.date.submitted2022-02-09T20:12:09Zen_US
dc.degree.disciplinePharmacyen_US
dc.degree.levelDoctor of Philosophy (Ph.D.)en_US
dc.description.abstractPoly(ADP-Ribose)Polymerase (PARP) is a family of 17 protein isomers that are involved in many cellular activities including DNA repair and apoptosis. Competitive inhibitors of the PARP family are used to mimic the endogenous substrate NAD+ and disrupt PARylation. The inhibition of PARP is used for therapeutic purposes such as anticancer therapy. These inhibitors can be used as anticancer drugs individually or in combination with other treatments. PJ34 is a non-selective PARP inhibitor based on a 6-(5H)-phenanthridinone ring system with moderate potency that is widely used for studying PARP function. In this study, a new series of phenanthridinone-based PARP inhibitors have been successfully developed guided by in silico methods. Through in silico methods, we were able to design inhibitors with novel structures to interact with designated amino acid residues of the PARP enzyme. We present two scaffolds to produce novel and potent PARP inhibitors: The first scaffold docks into the nicotinamide binding site and the phosphate binding site while interacting with D766 or D770 using a hydroxyl arm. The second scaffold docks into the nicotinamide binding site and the adenine binding site while interacting with R878 D766 or D770 with warheads. In vitro enzymatic studies indicated that our potent PARP inhibitors that were ~10-fold more potent than the original benchmark PJ34 and similar in potency to the benchmark olaparib. Our enzymatic assay results also verified that designs of a pair of enantiomers, selectively interacting with D766 in PARP1 and E335 in PARP2 (based on the in silico prediction), were able to achieve PARP1/PARP2 preference with better PARP2-selectivity than PJ34/olaparib. Cellular assay results also suggested that 2 out of our top 3 inhibitors were able to have equivalent or better synergistic effects in combination with anticancer drug temozolomide (TMZ), when compared to olaparib/TMZ. We proposed that while our phenanthridinone-based inhibitors worked in the same manner as olaparib, our champion inhibitor based on thienoquinolinone with de novo design might be able to potentiate TMZ by both PARP-trapping and strong catalytic inhibition. Overall, using phenanthridinone and thienoquinolinone as core components, we were able to develop best-in-series PARP inhibitors which are promising for future development.en_US
dc.description.noteMarch 2022en_US
dc.identifier.citationMLAen_US
dc.identifier.urihttp://hdl.handle.net/1993/36295
dc.language.isoengen_US
dc.rightsopen accessen_US
dc.subjectPARPen_US
dc.subjectCADDen_US
dc.subjectDrug designen_US
dc.subjectOrganic synthesisen_US
dc.subjectEnzymatic assayen_US
dc.titleDevelopment of novel PARP inhibitors based on phenanthridinones using computer-aided drug designen_US
dc.typedoctoral thesisen_US
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