Characterization of an inhibitory dynamic pharmacophore for the ERCC1-XPA interaction using a combined molecular dynamics and virtual screening approach.
Combination chemotherapy involving Cisplatin is a standard treatment for many cancers. However, following an initial positive response, patients will often relapse, presenting with Cisplatin-resistant disease. One possible mechanism for the acquired resistance to Cisplatin is an increase in DNA repair through the up-regulation of ERCC1, an essential component of the nucleotide excision repair complex. Recruitment of ERCC1 to the site of DNA damage is coordinated through its interaction with a protein known as XPA. As there are currently no effective inhibitors of this interaction, inhibition of the ERCC1/XPA interaction may provide an effective strategy for overcoming the development of Cisplatin-resistant cancers. To discover small molecule inhibitors of this interaction, we have screened both the NCI diversity set of ligands and DrugBank-small molecules against the XPA binding site in ERCC1. These compounds were screened using two different techniques in AUTODOCK to account for receptor flexibility. First, using a set of flexible residues, as determined from MD simulations of the XPA/ERCC1 complex and second, using the relaxed complex scheme implemented by performing independent docking experiments against an ensemble of target conformations that were generated from MD simulations. Lowest energy poses from the two different methods were then used to construct a pharmacophore model, which was then validated by comparison to UCN-01, a weak inhibitor of ERCC1 mediated nucleotide excision.
Barakat
Khaled H
KH
Department of Physics, University of Alberta, Edmonton, AB, Canada.
Torin Huzil
J
J
Luchko
Tyler
T
Jordheim
Lars
L
Dumontet
Charles
C
Tuszynski
Jack
J
D000970:Antineoplastic Agents / Q000627:therapeutic use; D001665:Binding Sites; D002945:Cisplatin / Q000627:therapeutic use; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D004720:Endonucleases / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D056004:Molecular Dynamics Simulation; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D025341:Principal Component Analysis; D011485:Protein Binding; D051760:Xeroderma Pigmentosum Group A Protein / Q000737:chemistry / Q000378:metabolism*
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; C497314:XPA protein, human; D051760:Xeroderma Pigmentosum Group A Protein; C071447:ERCC1 protein, human; D004720:Endonucleases; D002945:Cisplatin