Ligand conformational and solvation/desolvation free energy in protein-ligand complex formation.

In this study, an extensive sampling of the conformational space of nine HIV-1 protease inhibitors was performed to estimate the uncertainty with which a single-conformation scoring scheme approximates the ligand-protein binding free energy. The SMD implicit solvation/desolvation energy and gas-phase PM6-DH2 energy were calculated for a set of 1600 conformations of each ligand. The probability density functions of the energies were compared with the values obtained from the single-conformation approach and from a short ab initio molecular dynamics simulation. The relative uncertainty in the score within the set of nine inhibitors was calculated to be 3.5 kcal·mol(-1) and 2.7 kcal·mol(-1) for the single-conformation and short dynamics, respectively. These results, though limited to the consideration of flexible ligands, provide a valuable insight into the precision of rigid models in the current computer-aided drug design.

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

[2]  Yuko Okamoto,et al.  Dependency of ligand free energy landscapes on charge parameters and solvent models , 2010, J. Comput. Aided Mol. Des..

[3]  Carsten Kutzner,et al.  GROMACS 4:  Algorithms for Highly Efficient, Load-Balanced, and Scalable Molecular Simulation. , 2008, Journal of chemical theory and computation.

[4]  M. Murcko,et al.  Crystal Structure of HIV-1 Protease in Complex with Vx-478, a Potent and Orally Bioavailable Inhibitor of the Enzyme , 1995 .

[5]  J. Hašek,et al.  Role of hydroxyl group and R/S configuration of isostere in binding properties of HIV-1 protease inhibitors. , 2004, European journal of biochemistry.

[6]  Araz Jakalian,et al.  Fast, efficient generation of high‐quality atomic charges. AM1‐BCC model: I. Method , 2000 .

[7]  I. Pichová,et al.  Configurations of diastereomeric hydroxyethylene isosteres strongly affect biological activities of a series of specific inhibitors of human-immunodeficiency-virus proteinase. , 1997, European journal of biochemistry.

[8]  Celia A Schiffer,et al.  Discovery and selection of TMC114, a next generation HIV-1 protease inhibitor. , 2005, Journal of medicinal chemistry.

[9]  Benoît Roux,et al.  Computations of Absolute Solvation Free Energies of Small Molecules Using Explicit and Implicit Solvent Model. , 2009, Journal of chemical theory and computation.

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

[11]  H. C. Andersen.  Molecular dynamics simulations at constant pressure and/or temperature , 1980 .

[12]  S. Vasavanonda,et al.  ABT-538 is a potent inhibitor of human immunodeficiency virus protease and has high oral bioavailability in humans. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

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

[14]  Clemens C. J. Roothaan,et al.  New Developments in Molecular Orbital Theory , 1951 .

[15]  Christopher I. Bayly,et al.  Fast, efficient generation of high‐quality atomic charges. AM1‐BCC model: II. Parameterization and validation , 2002, J. Comput. Chem..

[16]  Jonathan W. Essex,et al.  A review of protein-small molecule docking methods , 2002, J. Comput. Aided Mol. Des..

[17]  J. Urban,et al.  Reduced‐bond tight‐binding inhibitors of HIV‐1 protease Fine tuning of the enzyme subsite specificity , 1992, FEBS letters.

[18]  Maureen M Goodenow,et al.  Analysis of HIV-1 CRF_01 A/E protease inhibitor resistance: structural determinants for maintaining sensitivity and developing resistance to atazanavir. , 2006, Biochemistry.

[19]  Jindřich Fanfrlík,et al.  Semiempirical Quantum Chemical PM6 Method Augmented by Dispersion and H-Bonding Correction Terms Reliably Describes Various Types of Noncovalent Complexes. , 2009, Journal of chemical theory and computation.

[20]  J. Hašek,et al.  Hydroxyethylamine isostere of an HIV-1 protease inhibitor prefers its amine to the hydroxy group in binding to catalytic aspartates. A synchrotron study of HIV-1 protease in complex with a peptidomimetic inhibitor. , 2002, Journal of medicinal chemistry.

[21]  Irene T Weber,et al.  Effect of flap mutations on structure of HIV-1 protease and inhibition by saquinavir and darunavir. , 2008, Journal of molecular biology.

[22]  Pär Söderhjelm,et al.  Conformational dependence of charges in protein simulations , 2009, J. Comput. Chem..

[23]  J F Davies,et al.  Viracept (nelfinavir mesylate, AG1343): a potent, orally bioavailable inhibitor of HIV-1 protease. , 1997, Journal of medicinal chemistry.

[24]  J. Kirkwood.  Statistical Mechanics of Fluid Mixtures , 1935 .

[25]  Pavel Hobza,et al.  A reliable docking/scoring scheme based on the semiempirical quantum mechanical PM6-DH2 method accurately covering dispersion and H-bonding: HIV-1 protease with 22 ligands. , 2010, The journal of physical chemistry. B.

[26]  Michal Otyepka,et al.  Transferable scoring function based on semiempirical quantum mechanical PM6-DH2 method: CDK2 with 15 structurally diverse inhibitors , 2011, J. Comput. Aided Mol. Des..

[27]  Matthew P. Repasky,et al.  Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. , 2006, Journal of medicinal chemistry.

[28]  S. Nosé.  A molecular dynamics method for simulations in the canonical ensemble , 1984 .

[29]  Pavel Hobza,et al.  A Transferable H-Bonding Correction for Semiempirical Quantum-Chemical Methods. , 2010, Journal of chemical theory and computation.

[30]  M. Parrinello,et al.  Polymorphic transitions in single crystals: A new molecular dynamics method , 1981 .

[31]  Hoover,et al.  Canonical dynamics: Equilibrium phase-space distributions. , 1985, Physical review. A, General physics.

[32]  V. Stoll,et al.  X-ray crystallographic structure of ABT-378 (lopinavir) bound to HIV-1 protease. , 2002, Bioorganic & medicinal chemistry.

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

[34]  E. Shakhnovich,et al.  SMoG: de Novo Design Method Based on Simple, Fast, and Accurate Free Energy Estimates. 1. Methodology and Supporting Evidence , 1996 .

[35]  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.

[36]  L. Kuo,et al.  Rapid X-ray diffraction analysis of HIV-1 protease-inhibitor complexes: inhibitor exchange in single crystals of the bound enzyme. , 1998, Acta crystallographica. Section D, Biological crystallography.

[37]  Pedro Alexandrino Fernandes,et al.  Protein–ligand docking: Current status and future challenges , 2006, Proteins.

[38]  P. C. Hariharan,et al.  The influence of polarization functions on molecular orbital hydrogenation energies , 1973 .

[39]  Amedeo Caflisch,et al.  Library screening by fragment‐based docking , 2009, Journal of molecular recognition : JMR.

[40]  K. Merz,et al.  Large-scale validation of a quantum mechanics based scoring function: predicting the binding affinity and the binding mode of a diverse set of protein-ligand complexes. , 2005, Journal of medicinal chemistry.

[41]  R. Zwanzig.  High‐Temperature Equation of State by a Perturbation Method. I. Nonpolar Gases , 1954 .

[42]  J. Urban,et al.  Specificity mapping of HIV-1 protease by reduced bond inhibitors. , 1993, Archives of biochemistry and biophysics.

[43]  W. L. Jorgensen.  Quantum and statistical mechanical studies of liquids. 10. Transferable intermolecular potential functions for water, alcohols, and ethers. Application to liquid water , 2002 .