Nonfitting protein–ligand interaction scoring function based on first‐principles theoretical chemistry methods: Development and application on kinase inhibitors

Targeted therapy is currently a hot topic in the fields of cancer research and drug design. An important requirement for this approach is the development of potent and selective inhibitors for the identified target protein. However, current ways to estimate inhibitor efficacy rely on empirical protein–ligand interaction scoring functions which, suffering from their heavy parameterizations, often lead to a low accuracy. In this work, we develop a nonfitting scoring function, which consists of three terms: (1) gas‐phase protein‐ligand binding enthalpy obtained by the eXtended ONIOM hybrid method based on an integration of density functional theory (DFT) methods (XYG3 and ωB97X‐D) and the semiempirical PM6 method, (2) solvation free energy based on DFT‐SMD solvation model, and (3) entropy effect estimated by using DFT frequency analysis. The new scoring function is tested on a cyclin‐dependent kinase 2 (CDK2) inhibitor database including 76 CDK2 protein inhibitors and a p21‐activated kinase 1 (PAK1) inhibitor database including 20 organometallic PAK1 protein inhibitors. From the results, good correlations are found between the calculated scores and the experimental inhibitor efficacies with the square of correlation coefficient R2 of 0.76–0.88. This suggests a good predictive power of this scoring function. To the best of our knowledge, this is the first high level theory‐based nonfitting scoring function with such a good level of performance. This scoring function is recommended to be used in the final screening of lead structure derivatives. © 2013 Wiley Periodicals, Inc.

[1]  Wenping Guo,et al.  XO: An extended ONIOM method for accurate and efficient modeling of large systems , 2012, J. Comput. Chem..

[2]  J. Pople,et al.  Self—Consistent Molecular Orbital Methods. XII. Further Extensions of Gaussian—Type Basis Sets for Use in Molecular Orbital Studies of Organic Molecules , 1972 .

[3]  M. Head‐Gordon,et al.  Long-range corrected hybrid density functionals with damped atom-atom dispersion corrections. , 2008, Physical chemistry chemical physics : PCCP.

[4]  H. Stoll,et al.  Energy-adjustedab initio pseudopotentials for the second and third row transition elements , 1990 .

[5]  Wange Lu,et al.  Structure of PAK1 in an Autoinhibited Conformation Reveals a Multistage Activation Switch , 2000, Cell.

[6]  Weiliang Zhu,et al.  C-X...H contacts in biomolecular systems: how they contribute to protein-ligand binding affinity. , 2009, The journal of physical chemistry. B.

[7]  Carlo Adamo,et al.  Influence of the Formation of the Halogen Bond ArX- - -N on the Mechanism of Diketonate Ligated Copper-Catalyzed Amination of Aromatic Halides , 2012 .

[8]  Fangfang Wang,et al.  Development of in silico models for pyrazoles and pyrimidine derivatives as cyclin-dependent kinase 2 inhibitors. , 2011, Journal of molecular graphics & modelling.

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

[10]  Eamonn F. Healy,et al.  Development and use of quantum mechanical molecular models. 76. AM1: a new general purpose quantum mechanical molecular model , 1985 .

[11]  S. Papson.  “Model” , 1981 .

[12]  Victor Guallar,et al.  Peripheral heme substituents control the hydrogen-atom abstraction chemistry in cytochromes P450 , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[13]  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 .

[14]  Neil A Burton,et al.  Modelling the binding of HIV-reverse transcriptase and nevirapine: an assessment of quantum mechanical and force field approaches and predictions of the effect of mutations on binding. , 2010, Physical chemistry chemical physics : PCCP.

[15]  Kenneth M. Merz,et al.  Fully Quantum Mechanical Description of Proteins in Solution. Combining Linear Scaling Quantum Mechanical Methodologies with the Poisson−Boltzmann Equation , 1999 .

[16]  Ronen Marmorstein,et al.  Targeting large kinase active site with rigid, bulky octahedral ruthenium complexes. , 2008, Journal of the American Chemical Society.

[17]  N. Gray,et al.  Targeting cancer with small molecule kinase inhibitors , 2009, Nature Reviews Cancer.

[18]  J. Stewart.  Optimization of parameters for semiempirical methods V: Modification of NDDO approximations and application to 70 elements , 2007, Journal of molecular modeling.

[19]  Julio Caballero,et al.  Computational Study of the Interactions between Guanine Derivatives and Cyclin-Dependent Kinase 2 (CDK2) by CoMFA and QM/MM , 2010, J. Chem. Inf. Model..

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

[21]  S. L. Dixon,et al.  Semiempirical molecular orbital calculations with linear system size scaling , 1996 .

[22]  Ping-Hua Sun,et al.  3D-QSAR and docking studies on pyrazolo[4,3-h]qinazoline-3-carboxamides as cyclin-dependent kinase 2 (CDK2) inhibitors. , 2010, Bioorganic & medicinal chemistry letters.

[23]  P. Cohen.  Protein kinases — the major drug targets of the twenty-first century? , 2002, Nature reviews. Drug discovery.

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

[25]  Anupama E. Gururaj,et al.  p21-activated kinases in cancer , 2006, Nature Reviews Cancer.

[26]  J. Duca,et al.  Recent advances on structure-informed drug discovery of cyclin-dependent kinase-2 inhibitors. , 2009, Future medicinal chemistry.

[27]  G. Shapiro,et al.  Cyclin-dependent kinase pathways as targets for cancer treatment. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[28]  A. Caflisch,et al.  Is quantum mechanics necessary for predicting binding free energy? , 2008, Journal of medicinal chemistry.

[29]  S. Grimme.  Semiempirical hybrid density functional with perturbative second-order correlation. , 2006, The Journal of chemical physics.

[30]  W. R. Wadt,et al.  Ab initio effective core potentials for molecular calculations. Potentials for K to Au including the outermost core orbitals , 1985 .

[31]  Julio Caballero,et al.  Binding Studies and Quantitative Structure–Activity Relationship of 3‐Amino‐1H‐Indazoles as Inhibitors of GSK3β , 2011, Chemical biology & drug design.

[32]  K. Merz,et al.  A quantum mechanics-based scoring function: study of zinc ion-mediated ligand binding. , 2004, Journal of the American Chemical Society.

[33]  Supa Hannongbua,et al.  Binding of huperzine A and galanthamine to acetylcholinesterase, based on ONIOM method. , 2011, Nanomedicine : nanotechnology, biology, and medicine.

[34]  A Wlodawer,et al.  Inhibitors of HIV-1 protease: a major success of structure-assisted drug design. , 1998, Annual review of biophysics and biomolecular structure.

[35]  D. Truhlar,et al.  The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals , 2008 .

[36]  Igor Ying Zhang,et al.  Doubly hybrid density functional for accurate description of thermochemistry, thermochemical kinetics and nonbonded interactions , 2011 .

[37]  Kenneth M Merz,et al.  A Mixed QM/MM Scoring Function to Predict Protein-Ligand Binding Affinity. , 2010, Journal of chemical theory and computation.

[38]  Fernando D. González Nilo,et al.  Insights into the Structural Basis of N2 and O6 Substituted Guanine Derivatives as Cyclin-Dependent Kinase 2 (CDK2) Inhibitors: Prediction of the Binding Modes and Potency of the inhibitors by Docking and ONIOM Calculations , 2009, J. Chem. Inf. Model..

[39]  Igor Ying Zhang,et al.  Extending the reliability and applicability of B3LYP. , 2010, Chemical communications.

[40]  J. Pople,et al.  Self‐consistent molecular orbital methods. XX. A basis set for correlated wave functions , 1980 .

[41]  Gernot Frenking,et al.  Structurally sophisticated octahedral metal complexes as highly selective protein kinase inhibitors. , 2011, Journal of the American Chemical Society.

[42]  Anan Wu,et al.  XO: An extended ONIOM method for accurate and efficient geometry optimization of large molecules , 2010 .

[43]  Huanxiang Liu,et al.  A novel method for protein‐ligand binding affinity prediction and the related descriptors exploration , 2009, J. Comput. Chem..

[44]  W. Goddard,et al.  Doubly hybrid density functional for accurate descriptions of nonbond interactions, thermochemistry, and thermochemical kinetics , 2009, Proceedings of the National Academy of Sciences.

[45]  C. Cramer,et al.  Universal solvation model based on solute electron density and on a continuum model of the solvent defined by the bulk dielectric constant and atomic surface tensions. , 2009, The journal of physical chemistry. B.