title: New design of nucleotide excision repair (NER) inhibitors for combination cancer therapy.
abstract: Many cancer chemotherapy agents act by targeting the DNA of cancer cells, causing substantial damage within their genome and causing them to undergo apoptosis. An effective DNA repair pathway in cancer cells can act in a reverse way by removing these drug-induced DNA lesions, allowing cancer cells to survive, grow and proliferate. In this context, DNA repair inhibitors opened a new avenue in cancer treatment, by blocking the DNA repair mechanisms from removing the chemotherapy-mediated DNA damage. In particular, the nucleotide excision repair (NER) involves more than thirty protein-protein interactions and removes DNA adducts caused by platinum-based chemotherapy. The excision repair cross-complementation group 1 (ERCC1)-xeroderma pigmentosum, complementation group A (XPA) protein (XPA-ERCC1) complex seems to be one of the most promising targets in this pathway. ERCC1 is over expressed in cancer cells and the only known cellular function so far for XPA is to recruit ERCC1 to the damaged point. Here, we build upon our recent advances in identifying inhibitors for this interaction and continue our efforts to rationally design more effective and potent regulators for the NER pathway. We employed in silico drug design techniques to: (1) identify compounds similar to the recently discovered inhibitors, but more effective at inhibiting the XPA-ERCC1 interactions, and (2) identify different scaffolds to develop novel lead compounds. Two known inhibitor structures have been used as starting points for two ligand/structure-hybrid virtual screening approaches. The findings described here form a milestone in discovering novel inhibitors for the NER pathway aiming at improving the efficacy of current platinum-based therapy, by modulating the XPA-ERCC1 interaction.
authors.affiliation: Department of Physics, University of Alberta, Edmonton, AB, Canada.
authors.forename: Francesco
authors.initials: F
authors.lastname: Gentile
authors.affiliation: Department of Physics, University of Alberta, Edmonton, AB, Canada; Department of Oncology, University of Alberta, Edmonton, AB, Canada.
authors.forename: Jack A
authors.initials: JA
authors.lastname: Tuszynski
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada. Electronic address: kbarakat@ualberta.ca.
authors.forename: Khaled H
authors.initials: KH
authors.lastname: Barakat
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols; D001665:Binding Sites; D002945:Cisplatin / Q000737:chemistry / Q000494:pharmacology; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D015195:Drug Design; D055808:Drug Discovery; D004720:Endonucleases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D006860:Hydrogen Bonding; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology; D055672:Static Electricity; D013816:Thermodynamics; D051760:Xeroderma Pigmentosum Group A Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D054852:Small Molecule Libraries; C497314:XPA protein, human; D051760:Xeroderma Pigmentosum Group A Protein; C071447:ERCC1 protein, human; D004720:Endonucleases; D002945:Cisplatin
keywords: Cancer; DNA repair; Drug discovery; ERCC1; In silico modeling; XPA