Molecular modelling studies of binding of DACD derivatives into G-Quadruplex DNA: comparison of force field and quantum polarized ligand docking methods

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Subramanian, Arun Kumar ; Cardin, Christine J. (2012)
  • Publisher: Academic Sciences

The DNA G-qadruplexes are one of the targets being actively explored for anti-cancer therapy by inhibiting them through small molecules. This computational study was conducted to predict the binding strengths and orientations of a set of novel dimethyl-amino-ethyl-acridine (DACA) analogues that are designed and synthesized in our laboratory, but did not diffract in Synchrotron light.Thecrystal structure of DNA G-Quadruplex(TGGGGT)4(PDB: 1O0K) was used as target for their binding properties in our studies.We used both the force field (FF) and QM/MM derived atomic charge schemes simultaneously for comparing the predictions of drug binding modes and their energetics. This study evaluates the comparative performance of fixed point charge based Glide XP docking and the quantum polarized ligand docking schemes. These results will provide insights on the effects of including or ignoring the drug-receptor interfacial polarization events in molecular docking simulations, which in turn, will aid the rational selection of computational methods at different levels of theory in future drug design programs. Plenty of molecular modelling tools and methods currently exist for modelling drug-receptor or protein-protein, or DNA-protein interactionssat different levels of complexities.Yet, the capasity of such tools to describevarious physico-chemical propertiesmore accuratelyis the next step ahead in currentresearch.Especially, the usage of most accurate methods in quantum mechanics(QM) is severely restricted by theirtedious nature. Though the usage of massively parallel super computing environments resulted in a tremendous improvement in molecular mechanics (MM) calculations like molecular dynamics,they are still capable of dealing with only a couple of tens to hundreds of atoms for QM methods. One such efficient strategy that utilizes thepowers of both MM and QM are the QM/MM hybrid methods. Lately, attempts have been directed towards the goal of deploying several different QM methods for betterment of force field based simulations, but with practical restrictions in place. One of such methods utilizes the inclusion of charge polarization events at the drug-receptor interface, that is not explicitly present in the MM FF.
  • References (12)
    12 references, page 1 of 2

    Illingworth CJR, Morris GM, Parkes KEB, Snell CR, Renolds CAAssesing the role of polarization in docking.J PhysChem A2008;112:12157-12163.

    -49.0 -50.4 -47.3 -35.1 -45.8 -45.6 -36.5 -32.6 -35.9 -43.1 -38.2 -38.6 -39 -45.3 -42.0 -27.4 -28.4 -34.7 -25.0 -31.9 -34.3 -12.4 -21.5 -23.2 -5.0 -20.4 -22.4 -22.8 -44.8 -44.4 -4.8 -11.1 -14.6 -11.5 -22.5 -16.5 2. Cho AE, Rinaldo D Extension of QM/MM docking and its applications to metalloproteins.JComputChem2009;30:2609- 2616.

    3. Clark GR, Pytel PD, Squire CJ, Neidle S Structure of the first parallel DNA quadruplex-drug complex.J AmChemSoc2003;125:4066-4067.

    4. Glide, version 5.5, Schrӧdinger, Inc, New York, NY, 2009.

    5. Jaguar, version 7.8, Schr ӧdinger, Inc, New York, NY, 2011.

    6. Becke ADDensity-functional thermochemistry. III. The role of exact exchange.J ChemPhys1993;98:5648-5652.

    7. Lee C, Yang W, Parr RG Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density.Phys Rev B 1998;37:785-789.

    8. Vosko SH, Wilk L, Nusair M Accurate spin-dependent electron liquid correlation energies for local spin density calculations: a critical analysis. Can J Phys1980;58:1200-1211.

    9. Stephens PJ, Devlin FJ, Chabalowski CF, Frish MJAb initio calculation of vibrational absorption and circular dichroism spectra using density functional force fields. J PhysChem 1994;98:11623-11627.

    10. LigPrep, version 2.5, Schrӧdinger, LLC, New York, NY, 2011.

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    1o0k Protein Data Bank
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