DNA Interactions of Polynuclear Platinum

Significant Achievements, Anticipated Outcomes and Future Work

In 2002 non-relativistic density functional calculations using ZORA basis sets were performed on 1,1/t,t, 1,0,1/t,t,t and 0,0,0/t,t,t. In all cases geometry optimisation was achieved and reasonable charges were obtained. In 2003 relativistic scalar ZORA calculations were attempted. Calculations for cisplatin and 1,1/t,t gave reasonable results. In the case of 1,1/t,t four calculations were performed and NMR tensors were calculated. Eleven relativistic scalar ZORA calculations have been performed on 1,0,1/t,t,t under different conditions. While geometry optimisation has been achieved in some cases, SCF convergence fails on the final step leading to erroneous charges, and this problem has not been solved as yet. Using charges calculated in MOPAC three 10 nanosecond and six 2 nanosecond molecular dynamics simulations with periodic boundary conditions have been performed in 2003. The three 10 nanosecond studied the interaction of 0,0,0/t,t,t with three different DNA sequences. In the 2 nanosecond simulations 3 new DNA sequences were introduced into the study. In total the four sequences investigated the relationship between base pair sequence and the directionality of the drug binding. The partial charge distribution for a variety of substituted 1,1/t,t and a new drug; 1,1/c,c, were determined using MOPAC2002. The standard chloro ligands were systematically substituted for water, acetate and phosphate. Comparison of LC vs. SC using the main calculation program, Sander, from the Amber7 suite. Started a timing/scaling comparison of both systems: 1,2,4 and CPUs on both LC and SC.

Work in 2004 will involve continuing the series of 10 nanosecond simulations using 1,0,1/t,t,t and possibly 1,1/t,t. Once these have been completed for semi-empirically (MOPAC) charges similar simulations will be performed on drugs whose charges have been calculated using density functional theory. Continuing the investigation into the substitution of these drugs in 2004 will involve the full parameterization of Amber7 for these new drug variants for eventual MD simulations studying their interactions with DNA.

Figure 1 Multinuclear platinum anticancer drugs studied using the APAC National Facility. a) 1,0,1/t,t,t b) 0,0,0/t,t,t c) 1,1/t,t d) 1,1/c,c.

Computational Techniques Used

The density functional theory calculations were performed on the program Amsterdam Density Functional (ADF). Geometry optimisations were performed on various polynuclear platinum anticancer drugs. These calculations were performed on the APAC National Facility because we did not have access to ADF on our computers. Molecular dynamics simulations were performed on the program Amber. To run 10 ns simulations in water requires significant computer power, which we did not have access to anywhere else.

Publications, Awards and External Funding

External Funding and Awards

The research is supported by an ARC Discovery grant ("DNA interactions of polynuclear platinum. Mechanistic NMR studies probing the origin of the unique antitumor activity of BBR3464", $290,000, 2002-4).

Publications

Long range 1.4- and 1,6-interstrand cross-links formed by a trinuclear platinum complex. Minor groove pre-association affects kinetics and mechanism of cross-link formation as well as adduct structure. A. Hegmans, S. J. Berners-Price, M. S. Davies, D. Thomas, A. S. Humphreys, N. Farrell. J. Am. Chem. Soc., 126, 2004, 2167-2180.
S. J. Berners-Price, M. S. Davies, J. W. Cox, D. S. Thomas, and N. Farrell, Competitive reactions of interstrand and interstrand DNA-Pt adducts: A dinuclear-platinum complex preferentially forms a 1,4-interstrand cross-link rather than a 1,2 intrastrand cross-link on binding to a GG 14-mer duplex, Chemistry--A European Journal, 9, 2003, 713-725.
D. S. Thomas, M. S. Davies, J. Zhang, S. J. Berners-Price, N. Farrell, NMR studies probing the directionality of DNA interstrand cross-linking by the trinuclear platinum complex BBR3464. Journal of Inorganic Biochemistry, 96, 2003, 239.
J. Zhang, D. S. Thomas, M. S. Davies, S. J. Berners-Price, N. Farrell, An examination of the aquation kinetics and equilibria of dinuclear platinum anticancer agents.. Journal of Inorganic Biochemistry, 96, 2003, 261.
M. S. Davies, S.J. Berners-Price, J.W. Cox and N. Farrell, The nature of the DNA template (single versus double-stranded) affects the rate of aquation of a dinuclear Pt anticancer drug. Chemical Communications, 2003, 122-123.

Conference Presentations

D. S. Thomas, S. J. Berners-Price, M. S. Davies, N. Farrell, NMR studies probing the directionality of DNA interstrand cross-linking by the trinuclear platinum complex BBR3464, ANZMAG 2004 Conference, Barossa Valley, February 2004.
J. J. Moniodis, D. S. Thomas, S. J. Berners-Price, N. Farrell, Electrostatic pre-association of tri-nuclear platinum anticancer drug BBR3464 with two 12-Mer DNA duplexes: an NMR and molecular modelling study, ANZMAG 2004 Conference, Barossa Valley, February 2004.
D. S. Thomas, S. J. Berners-Price, M. S. Davies, N. Farrell, NMR studies probing the directionality of DNA interstrand cross-linking by the trinuclear platinum complex BBR3464, 11th International Conference on Biological Inorganic Chemistry, Cairns, July 2003.
J. Zhang, D. S. Thomas, M. S. Davies, S. J. Berners-Price, N. Farrell, An examination of the aquation kinetics and equilibria of dinuclear platinum anticancer agents, 11th International Conference on Biological Inorganic Chemistry, Cairns, July 2003.
J. J. Moniodis, D. S. Thomas, S. J. Berners-Price, A. Hegmans, N. Farrell, DNA binding studies of the tri-nuclear platinum anticancer drug BBR3464: pre-association with a 12-Mer DNA duplex, RACI Inorganic Division Conference (IC03), Melbourne, February 2003.
J. J. Moniodis, D. S. Thomas, S. J. Berners-Price, A. Hegmans, N. Farrell, Studies of the pre-association of the trinuclear platinum anticancer drug BBR3464 with a 12-mer DNA duplex, Conference on Bioactive Discovery in the New Millennium, Lorne, Victoria, February 2003.