A QM/MM study of the binding of RAPTA ligands to cathepsin B

We have carried out quantum mechanical (QM) and QM/MM (combined QM and molecular mechanics) calculations, as well as molecular dynamics (MD) simulations to study the binding of a series of six RAPTA (Ru(II)-arene-1,3,5-triaza-7-phosphatricyclo-[3.3.1.1] decane) complexes with different arene substituents to cathepsin B. The recently developed QM/MM-PBSA approach (QM/MM combined with Poisson–Boltzmann solvent-accessible surface area solvation) has been used to estimate binding affinities. The QM calculations reproduce the antitumour activities of the complexes with a correlation coefficient (r2) of 0.35–0.86 after a conformational search. The QM/MM-PBSA method gave a better correlation (r2 = 0.59) when the protein was fixed to the crystal structure, but more reasonable ligand structures and absolute binding energies were obtained if the protein was allowed to relax, indicating that the ligands are strained when the protein is kept fixed. In addition, the best correlation (r2 = 0.80) was obtained when only the QM energies were used, which suggests that the MM and continuum solvation energies are not accurate enough to predict the binding of a charged metal complex to a charged protein. Taking into account the protein flexibility by means of MD simulations slightly improves the correlation (r2 = 0.91), but the absolute energies are still too large and the results are sensitive to the details in the calculations, illustrating that it is hard to obtain stable predictions when full flexible protein is included in the calculations.

[1]  R. Ahlrichs,et al.  Efficient molecular numerical integration schemes , 1995 .

[2]  Chung F Wong,et al.  Rank-ordering protein-ligand binding affinity by a quantum mechanics/molecular mechanics/Poisson-Boltzmann-surface area model. , 2007, The Journal of chemical physics.

[3]  Akash Khandelwal,et al.  A combination of docking, QM/MM methods, and MD simulation for binding affinity estimation of metalloprotein ligands. , 2005, Journal of medicinal chemistry.

[4]  P. Kollman,et al.  Atomic charges derived from semiempirical methods , 1990 .

[5]  R. Eldik,et al.  Kinetics and mechanism of the reduction of (ImH)[trans-RuCl4(dmso)(Im)] by ascorbic acid in acidic aqueous solution , 2007, JBIC Journal of Biological Inorganic Chemistry.

[6]  Lochana C. Menikarachchi,et al.  QM/MM approaches in medicinal chemistry research. , 2010, Current topics in medicinal chemistry.

[7]  M. Jakupec,et al.  From bench to bedside--preclinical and early clinical development of the anticancer agent indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019 or FFC14A). , 2006, Journal of inorganic biochemistry.

[8]  F. Jensen Introduction to Computational Chemistry , 1998 .

[9]  Roland H. Hertwig,et al.  On the parameterization of the local correlation functional. What is Becke-3-LYP? , 1997 .

[10]  Ulf Ryde,et al.  Comparison of methods for deriving atomic charges from the electrostatic potential and moments , 1998 .

[11]  Junmei Wang,et al.  Development and testing of a general amber force field , 2004, J. Comput. Chem..

[12]  P. Kollman,et al.  Calculating structures and free energies of complex molecules: combining molecular mechanics and continuum models. , 2000, Accounts of chemical research.

[13]  Pär Söderhjelm,et al.  On the Convergence of QM/MM Energies. , 2011, Journal of chemical theory and computation.

[14]  M. Peruzzini,et al.  Coordination chemistry of 1,3,5-triaza-7-phosphaadamantane (PTA) and derivatives. Part II. The quest for tailored ligands, complexes and related applications , 2010 .

[15]  P. Kollman,et al.  How well does a restrained electrostatic potential (RESP) model perform in calculating conformational energies of organic and biological molecules? , 2000 .

[16]  H. Berendsen,et al.  Molecular dynamics with coupling to an external bath , 1984 .

[17]  Jeremy C. Smith,et al.  Protein/ligand binding free energies calculated with quantum mechanics/molecular mechanics. , 2005, The journal of physical chemistry. B.

[18]  A. Bergamo,et al.  Down‐regulation of tumour gelatinase/inhibitor balance and preservation of tumour endothelium by an anti‐metastatic ruthenium complex , 1996, International journal of cancer.

[19]  M. Jakupec,et al.  Redox behavior of tumor-inhibiting ruthenium(III) complexes and effects of physiological reductants on their binding to GMP. , 2006, Dalton transactions.

[20]  Anne Milet,et al.  Exploring the Binding of Inhibitors Derived from Tetrabromobenzimidazole to the CK2 Protein Using a QM/MM-PB/SA Approach , 2009, J. Chem. Inf. Model..

[21]  P. Kollman,et al.  A well-behaved electrostatic potential-based method using charge restraints for deriving atomic char , 1993 .

[22]  I. Bratsos,et al.  A categorization of metal anticancer compounds based on their mode of action. , 2009, Dalton transactions.

[23]  W. R. Wadt,et al.  Ab initio effective core potentials for molecular calculations , 1984 .

[24]  A. Casini,et al.  Exploring metallodrug–protein interactions by mass spectrometry: comparisons between platinum coordination complexes and an organometallic ruthenium compound , 2009, JBIC Journal of Biological Inorganic Chemistry.

[25]  C. S. Allardyce,et al.  [Ru(η6-p-cymene)Cl2(pta)] (pta = 1,3,5-triaza-7-phosphatricyclo- [3.3.1.1]decane): a water soluble compound that exhibits pH dependent DNA binding providing selectivity for diseased cells , 2001 .

[26]  Christian G Hartinger,et al.  Bioorganometallic chemistry--from teaching paradigms to medicinal applications. , 2009, Chemical Society reviews.

[27]  A. Klamt,et al.  Refinement and Parametrization of COSMO-RS , 1998 .

[28]  Nathalie Reuter,et al.  Frontier Bonds in QM/MM Methods: A Comparison of Different Approaches , 2000 .

[29]  Marco Häser,et al.  Auxiliary basis sets to approximate Coulomb potentials (Chem. Phys. Letters 240 (1995) 283-290) , 1995 .

[30]  Florian Weigend,et al.  Auxiliary basis sets for main row atoms and transition metals and their use to approximate Coulomb potentials , 1997 .

[31]  Libero J. Bartolotti,et al.  Long range nonbonded attractive constants for some charged atoms , 1991 .

[32]  A. Casini,et al.  Reactivity of an antimetastatic organometallic ruthenium compound with metallothionein-2: relevance to the mechanism of action. , 2009, Metallomics : integrated biometal science.

[33]  Jacob Kongsted,et al.  Estimates of ligand-binding affinities supported by quantum mechanical methods , 2010, Interdisciplinary Sciences: Computational Life Sciences.

[34]  P. Kollman,et al.  A Second Generation Force Field for the Simulation of Proteins, Nucleic Acids, and Organic Molecules , 1995 .

[35]  P. Finn,et al.  Fast and accurate predictions of relative binding energies , 1997 .

[36]  Ranbir Singh,et al.  J. Mol. Struct. (Theochem) , 1996 .

[37]  M. Levitt,et al.  Theoretical studies of enzymic reactions: dielectric, electrostatic and steric stabilization of the carbonium ion in the reaction of lysozyme. , 1976, Journal of molecular biology.

[38]  T. Darden,et al.  Particle mesh Ewald: An N⋅log(N) method for Ewald sums in large systems , 1993 .

[39]  G. Scuseria,et al.  Climbing the density functional ladder: nonempirical meta-generalized gradient approximation designed for molecules and solids. , 2003, Physical review letters.

[40]  A. Klamt,et al.  COSMO : a new approach to dielectric screening in solvents with explicit expressions for the screening energy and its gradient , 1993 .

[41]  M J Clarke,et al.  Non-platinum chemotherapeutic metallopharmaceuticals. , 1999, Chemical reviews.

[42]  A. Bergamo,et al.  Influence of chemical stability on the activity of the antimetastasis ruthenium compound NAMI-A. , 2002, European journal of cancer.

[43]  Bonnie F. Sloane,et al.  Unraveling the role of proteases in cancer. , 2000, Clinica chimica acta; international journal of clinical chemistry.

[44]  G. Ciccotti,et al.  Numerical Integration of the Cartesian Equations of Motion of a System with Constraints: Molecular Dynamics of n-Alkanes , 1977 .

[45]  Hans W. Horn,et al.  Fully optimized contracted Gaussian basis sets for atoms Li to Kr , 1992 .

[46]  B. Keppler,et al.  Elucidation of the Interactions of an Anticancer Ruthenium Complex in Clinical Trials with Biomolecules Utilizing Capillary Electrophoresis Hyphenated to Inductively Coupled Plasma‐Mass Spectrometry. Short Communication , 2008, Chemistry & biodiversity.

[47]  P. Dyson,et al.  Metal-based antitumour drugs in the post genomic era. , 2006, Dalton transactions.

[48]  P. Kollman,et al.  Binding of a diverse set of ligands to avidin and streptavidin: an accurate quantitative prediction of their relative affinities by a combination of molecular mechanics and continuum solvent models. , 2000, Journal of medicinal chemistry.

[49]  Akash Khandelwal,et al.  QM/MM linear response method distinguishes ligand affinities for closely related metalloproteins , 2007, Proteins.

[50]  A. Casini,et al.  Gold compounds as anticancer agents: chemistry, cellular pharmacology, and preclinical studies , 2010, Medicinal research reviews.

[51]  Andrew D. Phillips,et al.  Coordination chemistry of 1,3,5-triaza-7-phosphaadamantane (PTA): Transition metal complexes and related catalytic, medicinal and photoluminescent applications , 2004 .

[52]  C. S. Allardyce,et al.  Hydrolysis study of the bifunctional antitumour compound RAPTA-C, [Ru(eta6-p-cymene)Cl2(pta)]. , 2008, Journal of inorganic biochemistry.

[53]  Andreas Klamt,et al.  COSMO Implementation in TURBOMOLE: Extension of an efficient quantum chemical code towards liquid systems , 2000 .

[54]  A. Casini,et al.  Rationalization of the inhibition activity of structurally related organometallic compounds against the drug target cathepsin B by DFT. , 2010, Dalton transactions.

[55]  J. Schellens,et al.  A Phase I and Pharmacological Study with Imidazolium-trans-DMSO-imidazole-tetrachlororuthenate, a Novel Ruthenium Anticancer Agent , 2004, Clinical Cancer Research.

[56]  D. Case,et al.  Exploring protein native states and large‐scale conformational changes with a modified generalized born model , 2004, Proteins.

[57]  P. Sadler,et al.  Organometallic chemistry, biology and medicine: ruthenium arene anticancer complexes. , 2005, Chemical communications.

[58]  Harald Lanig,et al.  Quantum mechanical/molecular mechanical (QM/MM) docking: an evaluation for known test systems , 2003 .

[59]  U. Ryde,et al.  QM/MM-PBSA method to estimate free energies for reactions in proteins. , 2008, The journal of physical chemistry. B.

[60]  G. Fuller,et al.  Down-regulation of cathepsin B expression impairs the invasive and tumorigenic potential of human glioblastoma cells , 2001, Oncogene.

[61]  M. L. Connolly Analytical molecular surface calculation , 1983 .

[62]  F. Weigend,et al.  Balanced basis sets of split valence, triple zeta valence and quadruple zeta valence quality for H to Rn: Design and assessment of accuracy. , 2005, Physical chemistry chemical physics : PCCP.

[63]  Chung F. Wong,et al.  SUPPLEMENTING THE PBSA APPROACH WITH QUANTUM MECHANICS TO STUDY THE BINDING BETWEEN CDK2 AND N2-SUBSTITUTED O6-CYCLOHEXYLMETHOXYGUANINE INHIBITORS , 2010 .

[64]  P. Dyson,et al.  In vitro and in vivo evaluation of ruthenium(II)-arene PTA complexes. , 2005, Journal of medicinal chemistry.

[65]  Ulf Ryde,et al.  The coordination of the catalytic zinc ion in alcohol dehydrogenase studied by combined quantum-chemical and molecular mechanics calculations , 1996, J. Comput. Aided Mol. Des..

[66]  A. Becke A New Mixing of Hartree-Fock and Local Density-Functional Theories , 1993 .

[67]  V. Hornak,et al.  Comparison of multiple Amber force fields and development of improved protein backbone parameters , 2006, Proteins.

[68]  W. L. Jorgensen,et al.  Comparison of simple potential functions for simulating liquid water , 1983 .

[69]  A. Casini,et al.  Emerging protein targets for anticancer metallodrugs: inhibition of thioredoxin reductase and cathepsin B by antitumor ruthenium(II)-arene compounds. , 2008, Journal of medicinal chemistry.

[70]  Bing Wang,et al.  The role of quantum mechanics in structure-based drug design. , 2007, Drug discovery today.

[71]  K. Morokuma,et al.  ONIOM: A Multilayered Integrated MO + MM Method for Geometry Optimizations and Single Point Energy Predictions. A Test for Diels−Alder Reactions and Pt(P(t-Bu)3)2 + H2 Oxidative Addition , 1996 .

[72]  Ulf Ryde,et al.  Structure, strain, and reorganization energy of blue copper models in the protein , 2001 .

[73]  Walter Thiel,et al.  QM/MM methods for biomolecular systems. , 2009, Angewandte Chemie.

[74]  Jan H. Jensen,et al.  Very fast empirical prediction and rationalization of protein pKa values , 2005, Proteins.

[75]  T. Darden,et al.  A smooth particle mesh Ewald method , 1995 .