Cisplatin is an important anti-cancer agent widely used in the clinic; however, it has several notable limitations. To develop novel platinum analogues, key characteristics were considered that may result in more effective platinum analogues. Herein results based on ab initio geometry optimizations (gas-and solution-phase) on cisplatin (1), oxaliplatin_1R_2R (2) and BNP3029 (3, a novel substituted cyano ligand-based platinum analogue, PtCl 2 [N≡C(CH 2) 3 (C 6 H 5)] 2) using the recently published potentials and basis sets for platinum are presented. Optimized quantum mechanical derived geometries of the 3 platinum agents were in good agreement with available experimental geometries. The reactivity of BNP3029 was compared to cisplatin by computing the activation free energy barriers for the attack of various nucleophiles on both 1 and 3 and their monoaquated derivatives. Based on the activation energy barriers, it was determined that: (i) the reaction rate may be similar for the attack of water on cisplatin and BNP3029; (ii) the reaction rate for the attack of DNA bases was slower for monoaquated BNP3029 compared to monoaquated cisplatin; and (iii) the reaction rates for a thiol/thiolate attack on monoaquated cisplatin or monoaquated BN3029 were similar. BNP3029 demonstrated potent cytotoxic activity in a variety of human cancer cell lines in comparison to cisplatin and oxaliplatin and also had potent cytotoxic activity in several platinum resistant cell lines.

and (vi) increased replicative bypass (or trans-lesion synthesis).In order to develop platinum analogues that overcome the aforementioned limitations, key characteristics were evaluated in studies reported herein, and a series of platinum analogues with substituted cyano groups as the carrier ligand were synthesized [5]. In an earlier study, ab initio computational studies on cisplatin, oxaliplatin and BNP3029 (Figure 1), a representative substituted cyano ligand from our novel platinum complexes [6], were reported. Herein, we present a comprehensive comparative computational study on the geometrical and morphological changes induced by cisplatin, oxaliplatin and BNP3029 upon binding to a 12-mer DNA oligonucleotide using molecular dynamics simulations with key findings described using Kolmogorov-Smirnov based statistical analyses [7]. Materials and Methods Molecular dynamics (MD) simulation: B-DNA and platinated-DNA with cisplatin, oxaliplatin and BNP3029MD simulations were carried out using the AMBER6.0 suite of programs [8] employing the parm99 forcefield. For a better description of α/γ backbone angle conformers in DNA, the parm99 forcefield was modified with the inclusion of parmbsc0 forcefield [9] AbstractCisplatin is an important anti-cancer agent widely used in the clinic; however, it has several notable limitations. To develop novel platinum analogues, key characteristics were considered that may result in more effective platinum analogues. In this study, we present comprehensive molecular dynamics simulation studies using a 12-mer DNA (5'-CCTCTggTCTCC-3', gg= the site of platination) oligonucleotide which was platinated with cisplatin (1), oxaliplatin_1R_2R (2), and BNP3029 (3, a novel substituted cyano platinum analogue, PtCl 2 [N≡C(CH 2 ) 3 (C 6 H 5 )] 2 ), and analyzed the large data output using the Kolmogorov-Smirnov statistical analyses. In summary, data indicated that BNP3029-DNA had less A-like DNA morphology in comparison to cisplatin-DNA and oxaliplatin-DNA thus maintaining a more B-like DNA form. BNP3029 demonstrated more potent cytotoxic activity, relative to cisplatin and oxaliplatin, in a variety of human cancer cell lines, including several platinum-resistant cell lines. 5'-TCTCCGGTCTCC-3' DNA sequence for B-DNA was used for each MD run. In the case of platinated-DNA, N7 atoms of the two guanines (gg) attach to platinum atom forming the platinum-DNA adduct (5'-TCTCCggTCTCC-3'). Published parameters for terms involving platinum with DNA bases (such as bond, angle and dihedral) were employed [10]. The only deviation from the published parameters was the use of 1.8 Å vdW radius for platinum in the current study based on the recommendation of smaller radius for platinum [11] compared to the 2.2 Å radius used in reference 10. J Phys Chem Total number of MD runsFor B-DNA, five separate runs were performed starting from the same topology and coordinates for the randomly generated initial velocities by using five different seeds. For four of the seeds, MD runs were performed for a period of 10 n...