Conformational Analysis of TMC114, a Novel HIV-1 Protease Inhibitor

TMC114, a potent novel HIV-1 protease inhibitor, remains active against a broad spectrum of mutant viruses. In order to bind to a variety of mutants, the compound needs to make strong, preferably backbone, interactions and have enough conformational flexibility to adapt to the changing geometry of the active site. The conformational analysis of TMC114 in the gas phase yielded 43 conformers in which five types of intramolecular H-bond interactions could be observed. All 43 conformers were subject to both rigid and flexible ligand docking in the wild-type and a triple mutant (L63P/V82T/I84V) of HIV-1 protease. The largest binding energy was calculated for the conformations that are close to the conformation observed in the X-ray complexes of TMC114 and HIV-1 protease.

[1]  A. Patick,et al.  Protease Inhibitors as Antiviral Agents , 1998, Clinical Microbiology Reviews.

[2]  Saul Wolfe,et al.  A COMPREHENSIVE APPROACH TO THE CONFORMATIONAL ANALYSIS OF CYCLIC COMPOUNDS , 1994 .

[3]  J. Mavri Irreversible inhibition of the HIV‐1 protease: A theoretical study , 1998 .

[4]  Celia A. Schiffer,et al.  Structural and Thermodynamic Basis for the Binding of TMC114, a Next-Generation Human Immunodeficiency Virus Type 1 Protease Inhibitor , 2004, Journal of Virology.

[5]  E. De Clercq,et al.  Toward improved anti-HIV chemotherapy: therapeutic strategies for intervention with HIV infections. , 1995, Journal of medicinal chemistry.

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

[7]  P. Kollman,et al.  Computational study of protein specificity: The molecular basis of HIV-1 protease drug resistance , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[8]  István Kolossváry,et al.  Low‐mode conformational search elucidated: Application to C39H80 and flexible docking of 9‐deazaguanine inhibitors into PNP , 1999 .

[9]  Thomas A. Halgren,et al.  Maximally diagonal force constants in dependent angle-bending coordinates. II. Implications for the design of empirical force fields , 1990 .

[10]  L. Rocheblave,et al.  Synthesis and antiviral activity of new anti-HIV amprenavir bioisosteres. , 2002, Journal of medicinal chemistry.

[11]  B. Brooks,et al.  HIV-1 Protease Cleavage Mechanism Elucidated with Molecular Dynamics Simulation , 1995 .

[12]  B. Tidor Molecular dynamics simulations , 1997, Current Biology.

[13]  Stanislav Miertus,et al.  Computational studies on tetrahydropyrimidine-2-one HIV-1 protease inhibitors: improving three-dimensional quantitative structure-activity relationship comparative molecular field analysis models by inclusion of calculated inhibitor- and receptor-based properties. , 2002, Journal of medicinal chemistry.

[14]  Y. Pommier,et al.  Cosalane analogues with enhanced potencies as inhibitors of HIV-1 protease and integrase. , 1995, Journal of medicinal chemistry.

[15]  C. D. Gelatt,et al.  Optimization by Simulated Annealing , 1983, Science.

[16]  Jacopo Tomasi,et al.  A new integral equation formalism for the polarizable continuum model: Theoretical background and applications to isotropic and anisotropic dielectrics , 1997 .

[17]  Joanna Trylska,et al.  Molecular dynamics simulations of the first steps of the reaction catalyzed by HIV-1 protease. , 2002, Biophysical journal.

[18]  U. Singh,et al.  A NEW FORCE FIELD FOR MOLECULAR MECHANICAL SIMULATION OF NUCLEIC ACIDS AND PROTEINS , 1984 .

[19]  R. Zauhar,et al.  Computational studies on HIV-1 protease inhibitors: influence of calculated inhibitor-enzyme binding affinities on the statistical quality of 3D-QSAR CoMFA models. , 2000, Journal of medicinal chemistry.

[20]  G. A. Petersson,et al.  A complete basis set model chemistry. II. Open‐shell systems and the total energies of the first‐row atoms , 1991 .

[21]  K Schulten,et al.  VMD: visual molecular dynamics. , 1996, Journal of molecular graphics.

[22]  Stephen R. Wilson,et al.  Applications of simulated annealing to the conformational analysis of flexible molecules , 1991 .

[23]  G. Chang,et al.  An internal-coordinate Monte Carlo method for searching conformational space , 1989 .

[24]  C. Levinthal,et al.  Predicting antibody hypervariable loop conformation. I. Ensembles of random conformations for ringlike structures , 1987, Biopolymers.

[25]  C. Debouck,et al.  Inhibition of human immunodeficiency virus 1 protease in vitro: rational design of substrate analogue inhibitors. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[26]  C. Alsenoy,et al.  brabo: a program for ab initio studies on large molecular systems , 1993 .

[27]  A. Wlodawer,et al.  Structure-based inhibitors of HIV-1 protease. , 1993, Annual review of biochemistry.

[28]  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.

[29]  István Kolossváry,et al.  Low Mode Search . An Efficient , Automated Computational Method for Conformational Analysis : Application to Cyclic and Acyclic Alkanes and Cyclic Peptides , 1997 .

[30]  C. Levinthal,et al.  Predicting antibody hypervariable loop conformations II: Minimization and molecular dynamics studies of MCPC603 from many randomly generated loop conformations , 1986, Proteins.

[31]  Akbar Nayeem,et al.  A comparative study of the simulated‐annealing and Monte Carlo‐with‐minimization approaches to the minimum‐energy structures of polypeptides: [Met]‐enkephalin , 1991 .

[32]  Alessandro Pedretti,et al.  VEGA: a versatile program to convert, handle and visualize molecular structure on Windows-based PCs. , 2002, Journal of molecular graphics & modelling.

[33]  M Karplus,et al.  The meaning of component analysis: decomposition of the free energy in terms of specific interactions. , 1995, Journal of molecular biology.

[34]  Arieh Warshel,et al.  Langevin Dipoles Model for ab Initio Calculations of Chemical Processes in Solution: Parametrization and Application to Hydration Free Energies of Neutral and Ionic Solutes and Conformational Analysis in Aqueous Solution , 1997 .

[35]  I B Duncan,et al.  Rational design of peptide-based HIV proteinase inhibitors. , 1990, Science.

[36]  G. A. Petersson,et al.  A complete basis set model chemistry. I. The total energies of closed‐shell atoms and hydrides of the first‐row elements , 1988 .

[37]  T. Meek Inhibitors of HIV-1 protease. , 1992, Journal of enzyme inhibition.

[38]  H. Berendsen,et al.  COMPUTER-SIMULATION OF MOLECULAR-DYNAMICS - METHODOLOGY, APPLICATIONS, AND PERSPECTIVES IN CHEMISTRY , 1990 .

[39]  Amalio Telenti,et al.  Drug resistance mutations in HIV-1. , 2003, Topics in HIV medicine : a publication of the International AIDS Society, USA.

[40]  P. Darke,et al.  L-735,524: an orally bioavailable human immunodeficiency virus type 1 protease inhibitor. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[41]  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.

[42]  Urban Bren,et al.  Decomposition of the solvation free energies of deoxyribonucleoside triphosphates using the free energy perturbation method. , 2006, The journal of physical chemistry. B.

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

[44]  A. Laaksonen,et al.  Visualization of solvation structures in liquid mixtures. , 1997, Journal of molecular graphics & modelling.

[45]  Werner Braun,et al.  Efficient search for all low energy conformations of polypeptides by Monte Carlo methods , 1991 .

[46]  H. Scheraga,et al.  Monte Carlo-minimization approach to the multiple-minima problem in protein folding. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[47]  Irene T Weber,et al.  High resolution crystal structures of HIV-1 protease with a potent non-peptide inhibitor (UIC-94017) active against multi-drug-resistant clinical strains. , 2004, Journal of molecular biology.

[48]  David S. Goodsell,et al.  Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function , 1998, J. Comput. Chem..

[49]  L Laaksonen,et al.  A graphics program for the analysis and display of molecular dynamics trajectories. , 1992, Journal of molecular graphics.

[50]  Vithal M. Kulkarni,et al.  Structure Based Prediction of Binding Affinity of Human Immunodeficiency Virus-1 Protease Inhibitors , 1999, J. Chem. Inf. Comput. Sci..