MDCisplatin

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Contents

General Information

  • Application's name: Molecular Design of Platinum Group Metal Complexes as Potential Non-classical Cisplatin Analogues
  • Application's acronym: MDCisplatin
  • Virtual Research Community: Computational Chemistry Applications
  • Scientific contact: Nicolay Dodoff, dodoff@obzor.bio21.bas.bg
  • Technical contact: Nicolay Dodoff, dodoff@obzor.bio21.bas.bg
  • Developers: Acad. Roumen Tsanev Institute of Molecular Biology-BAS, Bulgaria
  • Web site: http://wiki.hp-see.eu/index.php/MDCisplatin

Short Description

The search for novel metal-based carcinostatics with improved therapeutic characteristics with respect to the parent compound cisplatin remains a typical problem of biocoordination chemistry and anticancer drug design. The state-of-the-art in metalbased cytostatics becomes the design of non-conventional (non-classical) platinum complexes, differing considerably in their structure from cisplatin, displaying distinct mechanism of action, and, hence, quite promising for the treatment of cisplatin-resistant tumors. We have chosen the sulfonamides and thiosemicarbazones as suitable ligands forming platinum group metal complexes that are expected to give quite promising results in the light of the design of non-conventional metal-based cytostatics.

Problems Solved

Quantum chemical calculations at HF ab initio and DFT levels on platinum and other metal coordination compounds with expected or proved cytotoxic acivity. Geometry optimisation and estimation of conformational an spectroscopic properties.

Scientific and Social Impact

Elucidation of relationships between geometric and electronic structure, physicochemical properties and pharmacological activity of platinum an other metal coordination compounds.

Development of novel metal-based cytotoxic compound with potential significance for the chemotherapy of cancer.

Collaborations

  • Coordination Chemistry Laboratory (CCL), Institute of General and Inorganic Chemistry - BAS
  • Department of Chemistry, Aristotle University of Thessaloniki, Greece

Beneficiaries

  • Researchers from computational chemistry community

Number of users

3 number of users: access to Blue Gene/P and HPCG

Development Plan

  • Concept: M6
  • Start of alpha stage: M7-M12
  • Start of beta stage: M13-M16
  • Start of testing stage: M17 – M19
  • Start of deployment stage: M20-M22
  • Start of production stage: M24

Resource Requirements

  • Number of cores required for a single run: 16-32
  • Minimum RAM/core required: 1 GB
  • Storage space during a single run: 50 GB
  • Long-term data storage: 200 GB
  • Total core hours required: 50 000

Technical Features and HP-SEE Implementation

  • Primary programming language : FORTRAN/BASIC
  • Parallel programming paradigm : MPI/OpenMP
  • Main parallel code : GAUSSIAN, GAMESS
  • Pre/post processing code : Own program
  • Application tools and libraries : 256

Usage Example

In order to explore the capabilities of the free quantum-chemical software Firefly PCGamess, appropriate purely organic molecules were chosen, with the aid, on a later stage the program to be applied to metal-containing systems, like cisplatin analogues. The work done has thus an important methodological significance.

The endogenous peptides take part in the regulation of various adaptive reactions of the organism, including pain perception. The dipeptide kyotorphin (Tyr-Arg, Kyo) plays a role in pain modulation in the mammalian central nervous system (CNS), and is one of the most investigated neuropeptides. One of the successful strategies in the design of neuropeptides with enhanced stability and improved delivery to the CNS is that with the use of non-protein amino acids, like canavanive (Cav), a structural analogue and amtimetabolite of arginine (Arg). In our previous in vivo experiments we demonstrated that Tyr-Cav exerted a strong-reversible analgesic effect, more pronounced than that of Kyo. Bearing in mind these and the fact that norsulfoarginine (NsArg) is a structural analogue of arginine and canavanine, we synthesized a series of new peptides with expected analgesic activity, containing NsArg residues in their molecules: NsArg-Tyr, Tyr-NsArg, Tyr-NsArg-NH2 and Tyr-NsArg-OBzl. The conformational features of these dipeptides are of particular interest, both from theoretical and pharmacological point of view. Since no single-crystal X-ray diffraction data for the compounds are available until now, we undertook a quantum-chemical modelling of their structure. Here we present our preliminary computational results for Kyo (Figure 1) and NsArg-Tyr (Figure 2). Molecular mechanics (MM+ force field, HyperChem 7.5) conformational search for the two species was performed, and the global minimum-energy conformations thus obtained, were further optimized at HF ab initio (3-21G** basis set, Firefly PCGamess) level of theory. In both cases, specific, scorpion-like conformations are realized, with hydrogen bonds involving the guanidino-group and the phenolic hydroxyl.


Picture1.jpg               Picture2.jpg
       Figure 1                                   Figure 2

Infrastructure Usage

  • Home system: HPCG
    • Applied for access on: 10.2010
    • Access granted on: 11.2010
    • Achieved scalability: 32 cores
  • Accessed production systems:
  1. Blue Gene/P
    • Applied for access on: 10.2011
    • Access granted on: 11.2011
    • Achieved scalability: currently tested
  2. Currently applied for access to other HPC centers in HP-SEE.
    • Applied for access on: .
    • Access granted on: .
    • Achieved scalability: .
  • Porting activities: The application was porting to MPI using GAMESS application software on the HPCG cluster at IICT-BAS. A lot of MPI tests were done up to 32 cores to optimize the application.
  • Scalability studies: A good parallel efficiency is optained up to 32 cores on HPCG cluster. Some problems were solved considered different versions of Gamess software application.

Running on Several HP-SEE Centres

  • Benchmarking activities and results:
Processors Time (seconds)
16 2068
32 1452
64 1540

As it is seen the benchmarking is not so effective because currently the size of the problems is still small and that is why scalability is not effective beyond 32 cores.

  • Other issues: no

Achieved Results

A DFT conformational and vibrational analysis of a single molecule of cisplatin (cis-[Pt(NH3)2Cl2]) – the most widely used metal-based anticancer agent – was performed by means of PW91 functional and LANL08 ECP basis set for the Pt atom. 3-21G and 3-21G* Basis sets were used for the remaining atoms. All the initially chosen conformations were found to converge to the global minimum conformation of C2v symmetry with H atoms lying in the coordination plane and pointing to the Cl atoms. The computational results were compared with the newest experimental structural data and with the vibrational spectroscopic data for cisplatin, obtained by other workers. The chosen level of theory was found to describe satisfactory the molecular structure (r.m s. of the relative deviations 6%) and the harmonic vibrational frequencies (r.m s. of the relative deviations 5%) of cisplatin. The deviations of some calculated structural parameters from their experimental values were discussed in the light of the existence of extended hydrogen bonding network in the solid cisplatin. Parallel efficiency of the tasks on 16 CPU cores is twice better than on 8 CPU cores.

Picture3.png                             Picture4.png 
Figure 3. View of the seven non-equivalent and              Figure 4. View of the nine skeletal vibrations
non-enantiomorphic conformations of cisplatin               of cisplatin molecule with their symmetry.
arising from the combination in couples of the              The arrows represent the displacement vectors.
conformations a, b, b- and c. Each of them was 
subjected to DFT minimization.

Publications

  • T. Pajpanova, T. Dzimbova, N. I. Dodoff, “Molecular Modelling of the Dipeptides Kyotorphin and Norsulfoarginine-tyrosine”, Fifty Years Institute of Molecular Biology Roumen Tsanev, Anniversary Molecualar Biology Conference, October, 2011, accepted.
  • N. Dodoff, “A DFT/ECP-Small Basis Set Modelling of Cisplatin: Molecular Structure and Vibrational Spectrum”, Computational Molecular Bioscience, 2012, Volume 2, Number 2, pp. 35-44, (http://www.SciRP.org/journal/cmb), Published Online June 2012, doi:10.4236/cmb.2012.22004.

Proceedings

  • Nicolay I. Dodoff, Tatyana A. Dzimbova, Tamara I. Pajpanova, “Conformational Analysis and HF ab initio Geometry Optimization of Kyotorphine and Its Sulfo-Analogues Norsulfoarginine-Tyrosine and Tyrosine-Norsulfoarginine”, accepted for publication in HP-SEE UF Proceedings in Springer's series "Modeling and Optimization in Science and Technologies", 2013.

Presentations

  • N. I. Dodoff, “Molecular Modelling of the Dipeptides Kyotorphin and Norsulfoarginine-tyrosine”, Fifty Years Institute of Molecular Biology Roumen Tsanev, Anniversary Molecualar Biology Conference, October, 2011.
  • E. Atanassov, “Conformational Analysis of Kyotorphin Analogues Containing Unnatural Amino Acids”, poster presentation during HP-SEE User Forum 2012, October 17-19, Belgrade, Serbia.

Foreseen Activities

  • The foreseen activities involve further quantum chemical calculations on two main groups of pharmacologically important compounds. 1) Kyotorphine-like dipeptides -- molecular structure optimizations by HF and (or) DFT methods. 2) Pt(II) and (or) Pt(IV) complexes with sulfonamide ligands -- molecular structure and vibrational analysis".
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