Predicting the Binding Mode of Known NCp7 Inhibitors To Facilitate the Design of Novel Modulators

The HIV-1 nucleocapsid protein (NCp7) is an emerging target for antiretroviral therapy. Five hits have been reported to inhibit the NCp7-viral nucleic acids interaction at micromolar concentrations. We used two computationally refined structures of NCp7 as receptors to propose a reliable binding pose for these compounds, by means of computational methods. Theoretical binding modes are in agreement with available experimental data. Results lay the foundations for a rationale development of more effective NCp7 inhibitors.

[1]  P. Goodford.  A computational procedure for determining energetically favorable binding sites on biologically important macromolecules. , 1985, Journal of medicinal chemistry.

[2]  P A Kollman,et al.  Continuum solvent studies of the stability of RNA hairpin loops and helices. , 1998, Journal of biomolecular structure & dynamics.

[3]  Pavel Hobza,et al.  Theoretical Study on the Complexes of Benzene with Isoelectronic Nitrogen-Containing Heterocycles , 2008, Chemphyschem : a European journal of chemical physics and physical chemistry.

[4]  Yves Mély,et al.  How the HIV-1 nucleocapsid protein binds and destabilises the (-)primer binding site during reverse transcription. , 2008, Journal of molecular biology.

[5]  Zhihai Liu,et al.  Comparative Assessment of Scoring Functions on a Diverse Test Set , 2009, J. Chem. Inf. Model..

[6]  Harald Schwalbe,et al.  Inhibition of HIV‐1 by a Peptide Ligand of the Genomic RNA Packaging Signal Ψ , 2008, ChemMedChem.

[7]  P Willett,et al.  Development and validation of a genetic algorithm for flexible docking. , 1997, Journal of molecular biology.

[8]  A. Aldovini,et al.  Nucleocapsid and Matrix Protein Contributions to Selective Human Immunodeficiency Virus Type 1 Genomic RNA Packaging , 1998, Journal of Virology.

[9]  Robert J Fisher,et al.  Single DNA molecule stretching measures the activity of chemicals that target the HIV-1 nucleocapsid protein. , 2006, Analytical biochemistry.

[10]  R. Glen,et al.  Molecular recognition of receptor sites using a genetic algorithm with a description of desolvation. , 1995, Journal of molecular biology.

[11]  J. Irwin,et al.  Benchmarking sets for molecular docking. , 2006, Journal of medicinal chemistry.

[12]  Christopher R. Corbeil,et al.  Docking Ligands into Flexible and Solvated Macromolecules. 3. Impact of Input Ligand Conformation, Protein Flexibility, and Water Molecules on the Accuracy of Docking Programs , 2009, J. Chem. Inf. Model..

[13]  Peter A. Kollman,et al.  Calculating Structures and Free Energies of Complex Molecules: Combining Molecular Mechanics and Continuum Models , 2001 .

[14]  Fabrizio Manetti,et al.  Molecular Dynamics and DFT Study on HIV-1 Nucleocapsid Protein-7 in Complex with Viral Genome , 2010, J. Chem. Inf. Model..

[15]  W. L. Jorgensen,et al.  Development and Testing of the OPLS All-Atom Force Field on Conformational Energetics and Properties of Organic Liquids , 1996 .

[16]  David S. Goodsell,et al.  AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility , 2009, J. Comput. Chem..

[17]  R. Abagyan,et al.  Flexible ligand docking to multiple receptor conformations: a practical alternative. , 2008, Current opinion in structural biology.

[18]  Shan Cen,et al.  Roles of Pr55gag and NCp7 in tRNA3Lys Genomic Placement and the Initiation Step of Reverse Transcription in Human Immunodeficiency Virus Type 1 , 2000, Journal of Virology.

[19]  Jacques Haiech,et al.  Identification by high throughput screening of small compounds inhibiting the nucleic acid destabilization activity of the HIV-1 nucleocapsid protein. , 2009, Biochimie.

[20]  G. V. Paolini,et al.  Empirical scoring functions: I. The development of a fast empirical scoring function to estimate the binding affinity of ligands in receptor complexes , 1997, J. Comput. Aided Mol. Des..

[21]  Richard D. Taylor,et al.  Modeling water molecules in protein-ligand docking using GOLD. , 2005, Journal of medicinal chemistry.

[22]  Robin Taylor,et al.  Comparing protein–ligand docking programs is difficult , 2005, Proteins.

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

[24]  D. E. Clark,et al.  Flexible docking using tabu search and an empirical estimate of binding affinity , 1998, Proteins.

[25]  P. Borer,et al.  Structure of the HIV-1 nucleocapsid protein bound to the SL3 psi-RNA recognition element. , 1998, Science.

[26]  Steven W. Muchmore,et al.  Rapid Estimation of Relative Protein-Ligand Binding Affinities Using a High-Throughput Version of MM-PBSA , 2007, J. Chem. Inf. Model..

[27]  Wei Zhang,et al.  A point‐charge force field for molecular mechanics simulations of proteins based on condensed‐phase quantum mechanical calculations , 2003, J. Comput. Chem..

[28]  Jason C. Cole,et al.  Testing Assumptions and Hypotheses for Rescoring Success in Protein-Ligand Docking , 2009, J. Chem. Inf. Model..

[29]  G. McGaughey,et al.  pi-Stacking interactions. Alive and well in proteins. , 1998, The Journal of biological chemistry.

[30]  R C Wade,et al.  Identifying targets for bioreductive agents: using GRID to predict selective binding regions of proteins. , 1989, Journal of molecular graphics.

[31]  Zhihai Liu,et al.  Evaluation of the performance of four molecular docking programs on a diverse set of protein‐ligand complexes , 2010, J. Comput. Chem..