title: The use of molecular dynamics simulations to evaluate the DNA sequence-selectivity of G-A cross-linking PBD-duocarmycin dimers.
abstract: The pyrrolobenzodiazepine (PBD) and duocarmycin families are DNA-interactive agents that covalently bond to guanine (G) and adenine (A) bases, respectively, and that have been joined together to create synthetic dimers capable of cross-linking G-G, A-A, and G-A bases. Three G-A alkylating dimers have been reported in publications to date, with defined DNA-binding sites proposed for two of them. In this study we have used molecular dynamics simulations to elucidate preferred DNA-binding sites for the three published molecular types. For the PBD-CPI dimer UTA-6026 (1), our simulations correctly predicted its favoured binding site (i.e., 5'-C(G)AATTA-3') as identified by DNA cleavage studies. However, for the PBD-CI molecule ('Compound 11', 3), we were unable to reconcile the results of our simulations with the reported preferred cross-linking sequence (5'-ATTTTCC(G)-3'). We found that the molecule is too short to span the five base pairs between the A and G bases as claimed, but should target instead a sequence such as 5'-ATTTC(G)-3' with two less base pairs between the reacting G and A residues. Our simulation results for this hybrid dimer are also in accord with the very low interstrand cross-linking and in vitro cytotoxicity activities reported for it. Although a preferred cross-linking sequence was not reported for the third hybrid dimer ('27eS', 2), our simulations predict that it should span two base pairs between covalently reacting G and A bases (e.g., 5'-GTAT(A)-3').
authors.affiliation: Femtogenix Ltd, Britannia House, 7 Trinity Street, London SE1 1DB, United Kingdom; Institute of Pharmaceutical Science, King's College London, Britannia House, 7 Trinity Street, London SE1 1DB, United Kingdom.
authors.forename: Paul J M
authors.initials: PJM
authors.lastname: Jackson
authors.affiliation: Femtogenix Ltd, Britannia House, 7 Trinity Street, London SE1 1DB, United Kingdom; Institute of Pharmaceutical Science, King's College London, Britannia House, 7 Trinity Street, London SE1 1DB, United Kingdom.
authors.forename: Khondaker M
authors.initials: KM
authors.lastname: Rahman
authors.affiliation: Femtogenix Ltd, Britannia House, 7 Trinity Street, London SE1 1DB, United Kingdom; Institute of Pharmaceutical Science, King's College London, Britannia House, 7 Trinity Street, London SE1 1DB, United Kingdom.
authors.forename: David E
authors.initials: DE
authors.lastname: Thurston
mesh_terms: D001483:Base Sequence; D001569:Benzodiazepines / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003432:Cross-Linking Reagents / Q000737:chemistry / Q000494:pharmacology*; D004247:DNA / Q000737:chemistry* / Q000187:drug effects; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D000080890:Duocarmycins; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D003432:Cross-Linking Reagents; D000080890:Duocarmycins; D007211:Indoles; D008024:Ligands; D011758:Pyrroles; D011760:Pyrrolidinones; C438462:pyrrolo(2,1-c)(1,4)benzodiazepine; D001569:Benzodiazepines; D004247:DNA; C058289:duocarmycin A
keywords: CBI; CPI; DNA cross-linking; Duocarmycin; Molecular dynamics; PBD; PBD–CPI dimer; Pyrrolobenzodiazepine; Seco-amino CI