Role of Ligand Reorganization and Conformational Restraints on the Binding Free Energies of DAPY Non-Nucleoside Inhibitors to HIV Reverse Transcriptase

Emilio Gallicchio

BioMaPS Institute for Quantitative Biology, Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, USA.

DOI: 10.4236/cmb.2012.21002                

Abstract

The results of computer simulations of the binding of etravirine (TMC125) and rilpivirine (TMC278) to HIV reverse transcriptase are reported. It is confirmed that consistent binding free energy estimates are obtained with or without the application of torsional restraints when the free energies of imposing the restraints are taken into account. The restraints have a smaller influence on the thermodynamics and apparent kinetics of binding of TMC125 compared to the more flexible TMC278 inhibitor. The concept of the reorganization free energy of binding is useful to understand and categorize these effects. Contrary to expectations, the use of conformational restraints did not consistently enhance convergence of binding free energy estimates due to suppression of binding/unbinding pathways and due to the influence of rotational degrees of freedom not directly controlled by the restraints. Physical insights concerning the thermodynamic driving forces for binding and the role of “jiggling” and “wiggling” motion of the ligands are discussed. Based on these insights we conclude that an ideal inhibitor, if chemically realizable, would possess the electrostatic charge distribution of TMC125, so as to form strong interactions with the receptor, and the larger and more flexible substituents of TMC278, so as to minimize reorganization free energy penalties and the effects of resistance mutations, suitably modified, as in TMC125, so as to disfavor the formation of non-binding competent extended conformations when free in solution.

Keywords

HIV-RT; TMC125; TMC278; Etravirine; Rilpivirine; Binding Free Energy

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	W. L. Jorgensen, “The Many Roles of Computation in Drug Discovery,” Science, Vol. 303, No. 5665, 2004, pp. 1813-1818. doi:10.1126/science.1096361
[2]	O. Guvench and A. D. MacKerell, “Computational Evaluation of Protein-Small Molecule Binding,” Current Opinion in Structural Biology, Vol. 19, No. 1, 2009, pp. 56-61. doi:10.1016/j.sbi.2008.11.009
[3]	M. K. Gilson and H.-X. Zhou, “Calculation of Protein-Ligand Binding Affinities,” Annual Review of Biophysics and Biomolecular Structure, Vol. 36, 2007, pp. 21-42. doi:10.1146/annurev.biophys.36.040306.132550
[4]	M. R. Shirts, D. L. Mobley and J. D. Chodera, “Alchemical Free Energy Calculations: Ready for Prime Time?” Annual Reports in Computational Chemistry, Vol. 3, 2007, pp. 41-59. doi:10.1016/S1574-1400(07)03004-6
[5]	D. L. Mobley and K. A. Dil, “Binding of Small-Molecule Ligands to Proteins: ‘What You See’ Is Not Always ‘What You Get’,” Structure, Vol. 17, No. 4, 2009, pp. 489-498.
[6]	Y. Q. Deng and B. Roux, “Computations of Standard Binding Free Energies with Molecular Dynamics Simulations,” The Journal of Physical Chemistry B, Vol. 113, No. 8, 2009, pp. 2234-2246. doi:10.1021/jp807701h
[7]	J. D. Chodera, D. L. Mobley, M. R. Shirts, R. W. Dixon, K. Branson and V. S. Pande, “Alchemical Free Energy Methods for Drug Discovery: Progress and Challenges,” Current Opinion in Structural Biology, Vol. 21, No. 2, 2011, pp. 150-160.
[8]	E. Perola and P. S. Charifson, “Conformational Analysis of Drug-Like Molecules Bound to Proteins: An Extensive Study of Ligand Reorganization upon Binding,” Journal of Medicinal Chemistry, Vol. 47, No. 10, 2004, pp. 2499-2510. doi:10.1021/jm030563w
[9]	J. Liebeschuetz, J. Hennemann, T. Olsson and C. Groom, “The Good, the Bad and the Twisted: A Survey of Ligand Geometry in Protein Crystal Structures,” Journal of Computer-Aided Molecular Design, Vol. 26, No. 2, 2012, pp. 169-183.
[10]	M. Lapelosa, E. Gallicchio, G. F. Arnold, E. Arnold and R. M. Levy, “In Silico Vaccine Design Based on Molecular Simulations of Rhinovirus Chimeras Presenting HIV-1 GP41 Epitopes,” Journal of Molecular Biology, Vol. 385, No. 2, 2009, pp. 675-691. doi:10.1016/j.jmb.2008.10.089
[11]	M. Lapelosa, G. F. Arnold, E. Gallicchio, E. Arnold and R. M. Levy, “Antigenic Characteristics of Rhinovirus Chimeras Designed in Silico for Enhanced Presentation of HIV-1 GP41 Epitopes,” Journal of Molecular Biology, Vol. 397, No. 3, 2010, pp. 752-766. doi:10.1016/j.jmb.2010.01.064
[12]	J. E. DeLorbe, J. H. Clements, M. G. Teresk, A. P. Benfield, H. R. Plake, L. E. Millspaugh and S. F. Martin, “Thermodynamic and Structural Effects of Conformational Constraints in Protein-Ligand Interactions. Entropic Paradoxy Associated with Ligand Preorganization,” Journal of the American Chemical Society, Vol. 131, No. 46, 2009, pp. 16758-16770. doi:10.1021/ja904698q
[13]	M. Bizzarri, S. Marsili and P. Procacci, “Intraligand Hydrophobic Interactions Rationalize Drug Affinities for Peptidyl-Prolyl Cis-Trans Isomerase Protein,” The Journal of Physical Chemistry B, Vol. 115, No. 19, 2011, pp. 6193-6201. doi:10.1021/jp110585p
[14]	M. Bizzarri, E. Tenori, M. R. Martina, S. Marsili, G. Caminati, S. Menichetti and P. Procacci, “New Perspective on How and Why Immunophilin fk506-Related Ligands Work,” The Journal of Physical Chemistry Letters, Vol. 2, No. 22, 2011, pp. 2834-2839. doi:10.1021/jz201037u
[15]	C.-Y. Yang, H. Y. Sun, J. Y. Chen, Z. Nikolovska-Coleska and S. M. Wang, “Importance of Ligand Reorganization Free Energy in Protein-Ligand Binding-Affinity Prediction,” Journal of the American Chemical Society, Vol. 131, No. 38, 2009, pp. 13709-13721. doi:10.1021/ja9039373
[16]	C. Gao, M.-S. Park and H. A. Stern, “Accounting for Ligand Conformational Restriction in Calculations of Protein-Ligand Binding Affinities,” Biophysical Journal, Vol. 98, No. 5, 2010, pp. 901-910. doi:10.1016/j.bpj.2009.11.018
[17]	K. Andries, H. Azijn, T. Thielemans, D. Ludovici, M. Kukla, J. Heeres, P. Janssen, B. De Corte, J. Vingerhoets, R. Pauwels and M.-P. de Bthune, “Tmc125, a Novel Next-Generation Nonnucleoside Reverse Transcriptase Inhibitor Active Against Nonnucleoside Reverse Transcriptase Inhibitor-Resistant Human Immunodeficiency Virus Type 1,” Antimicrobial Agents and Chemotherapy, Vol. 48, No. 12, 2004, pp. 4680-4686. doi:10.1128/AAC.48.12.4680-4686.2004
[18]	P. A. J. Janssen, P. J. Lewi, E. Arnold, F. Daeyaert, M. de Jonge, J. Heeres, L. Koymans, M. Vinkers, J. Guillemont, E. Pasquier, M. Kukla, D. Ludovici, K. Andries, M.-P. de Bèthune, R. Pawels, K. Das, A. D. Clark Jr., Y. V. Frenkel, S. H. Hughes, B. Medaer, F. De Knaep, H. Bohets, F. De Clerck, A. Lampo, P. Williams and P. Stoffels, “In Search of a Novel Anti-HIV Drug: Multidisciplinary Coordination in the Discovery of 4-[[4-[[4-[(1e)-2-Cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitri
[19]	K. Das, A. D. Clark, P. J. Lewi, J. Heeres, M. R. De Jonge, L. M. H. Koymans, H. M. Vinkers, F. Daeyaert, D. W. Ludovici, M. J. Kukla, B. De Corte, R. W. Kavash, C. Y. Ho, H. Ye, M. A. Lichtenstein, K. Andries, R. Pauwels, M.-P. De Bthune, P. L. Boyer, P. Clark, S. H. Hughes, P. A. J. Janssen and E. Arnold, “Roles of Conformational and Positional Adaptability in Structure-Based Design of Tmc125-r165335 (Etravirine) and Related Non-Nucleo0 side Reverse Transcriptase Inhibitors That Are Highly Potent and Effe
[20]	K. Das, P. J. Lewi, S. H. Hughes and E. Arnold, “Crystallography and the Design of Anti-AIDS Drugs: Conformational Flexibility and Positional Adaptability Are Important in the Design of Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors,” Progress in Biophysics and Molecular Biology, Vol. 88, No. 2, 2005, pp. 209-231. doi:10.1016/j.pbiomolbio.2004.07.001
[21]	K. Das, J. D. Bauman, A. D. Clark, Y. V. Frenkel, P. J. Lewi, A. J. Shatkin, S. H. Hughes and E. Arnold, “High-Resolution Structures of HIV-1 Reverse Transcriptase/tmc278 Complexes: Strategic Flexibility Explains Potency against Resistance Mutations,” Proceedings of the National Academy of Sciences, Vol. 105, No. 5, 2008, pp. 1466-1471. doi:10.1073/pnas.0711209105
[22]	Y. V. Frenkel, A. D. Clark, K. Das, Y.-H. Wang, P. J. Lewi, P. A. J. Janssen and E. Arnold, “Concentration and pH Dependent Aggregation of Hydrophobic Drug Molecules and Relevance to Oral Bioavailability,” Journal of Medicinal Chemistry, Vol. 48, No. 6, 2005, pp. 1974-1983. doi:10.1021/jm049439i
[23]	Y. V. Frenkel, E. Gallicchio, K. Das, R. M. Levy and E. Arnold, “Molecular Dynamics Study of Non-Nucleoside Reverse Transcriptase Inhibitor 4-[[4-[[4-[(e)-2-Cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile (Tmc278/Rilpivirine) Aggregates: Correlation between Amphiphilic Properties of the Drug and Oral Bioavailability,” Journal of Medicinal Chemistry, Vol. 52, No. 19, 2009, pp. 5896-5905. doi:10.1021/jm900282z
[24]	H. Okumura, E. Gallicchio and R. M. Levy, “Conformational Populations of Ligand-Sized Molecules by Replica Exchange Molecular Dynamics and Temperature Reweighting,” Journal of Computational Chemistry, Vol. 31, 2010, pp. 1357-1367.
[25]	Y. Frenkel, “The Roles of Structural Variability and Amphiphilicity of TMC278/Rilpivirine in Mechanisms of HIV Drug Resistance Avoidance and Enhanced Oral Bioavailability,” PhD thesis, Rutgers University, Piscataway, 2009.
[26]	E. Gallicchio and R. M. Levy, “Advances in All Atom Sampling Methods for Modeling Protein-Ligand Binding Affinities,” Current Opinion in Structural Biology, Vol. 21, No. 2, 2011, pp. 161-166. doi:10.1016/j.sbi.2011.01.010
[27]	D. L. Mobley, “Let’s Get Honest about Sampling,” Journal of Computer-Aided Molecular Design, Vol. 26, No. 1, 2012, pp. 93-95. doi:10.1007/s10822-011-9497-y
[28]	M. Lapelosa, E. Gallicchio and R. M. Levy, “Conformational Transitions and Convergence of Absolute Binding Free Energy Calculations,” Journal of Chemical Theory and Computation, Vol. 8, 2012, pp. 47-60. doi:10.1021/ct200684b
[29]	E. Gallicchio and R. M. Levy, “Prediction of Sample Host-Guest Affinities with the Binding Energy Distribution Analysis Method (BEDAM),” Journal of Computer-Aided Molecular Design, 2012, in Press. doi:10.1007/s10822-012-9552-3
[30]	E. Gallicchio, M. Lapelosa and R. M. Levy, “Binding Energy Distribution Analysis Method (BEDAM) for Estimation of Protein-Ligand Binding Affinities,” Journal of Chemical Theory and Computation, Vol. 6, No. 9, 2010, pp. 2961-2977. doi:10.1021/ct1002913
[31]	D. L. Mobley, J. D. Chodera and K. A. Dill, “On the Use of Orientational Restraints and Symmetry Corrections in Alchemical Free Energy Calculations,” Journal of Chemical Physics, Vol. 125, No. 8, 2006, Article ID: 084902. doi:10.1063/1.2221683
[32]	D. L. Mobley, J. D. Chodera and K. A. Dill, “The Confine-and-Release Method: Obtaining Correct Binding Free Energies in the Presence of Protein Conformational Change,” Journal of Chemical Theory and Computation, Vol. 3, No. 4, 2007, pp. 1231-1235. doi:10.1021/ct700032n
[33]	E. B. Lansdon, K. M. Brendza, M. Hung, R. Wang, S. Mukund, D. Jin, G. Birkus, N. Kutty and X. H. Liu, “Crystal Structures of HIV-1 Reverse Transcriptase with Etravirine (TMC125) and Rilpivirine (TMC278): Implications for Drug Design,” Journal of Medicinal Chemistry, Vol. 53, No. 10, 2010, pp. 4295-4299. doi:10.1021/jm1002233
[34]	M. K. Gilson, J. A. Given, B. L. Bush and J. A. McCammon, “The Statistical-Thermodynamic Basis for Computation of Binding Affinities: A Critical Review,” Biophysical Journal, Vol. 72, 1997, pp. 1047-1069. doi:10.1016/S0006-3495(97)78756-3
[35]	F. P. Buelens and H. Grubmüller, “Linear-Scaling Soft-Core Scheme for Alchemical Free Energy Calculations,” Journal of Computational Chemistry, Vol. 33, No. 1, 2012, pp. 25-33. doi:10.1002/jcc.21938
[36]	M. R. Shirts and J. D. Chodera, “Statistically Optimal Analysis of Samples from Multiple Equilibrium States,” Journal of Chemical Physics, Vol. 129, No. 12, 2008, Article ID: 124105. doi:10.1063/1.2978177
[37]	E. Gallicchio and R. M. Levy, “Advances in Protein Chemistry and Structural Biology,” Recent Theoretical and Computational Advances for Modeling Protein-Ligand Binding Affinities, Academic Press, London, Vol. 85, 2011, pp. 27-80.
[38]	E. Gallicchio and R. M. Levy, “AGBNP: An Analytic Implicit Solvent Model Suitable for Molecular Dynamics Simulations and High-Resolution Modeling,” Journal of Computational Chemistry, Vol. 25, 2004, pp. 479-499. doi:10.1002/jcc.10400
[39]	E. Gallicchio, K. Paris and R. M. Levy, “The AGBNP2 Implicit Solvation Model,” Journal of Chemical Theory and Computation, Vol. 5, No. 9, 2009, pp. 2544-2564. doi:10.1021/ct900234u
[40]	W. L. Jorgensen, D. S. Maxwell and J. Tirado-Rives, “Developement and Testing of the OPLS All-Atom Force Field on Conformational Energetics and Properties of Organic Liquids,” Journal of the American Chemical Society, Vol. 118, 1996, pp. 11225-11236. doi:10.1021/ja9621760
[41]	G. A. Kaminski, R. A. Friesner, J. Tirado-Rives and W. L. Jorgensen, “Evaluation and Reparameterization of the OPLS-AA Force Field for Proteins via Comparison with Accurate Quantum Chemical Calculations on Peptides.” The Journal of Physical Chemistry B, Vol. 105, 2001, pp. 6474-6487. doi:10.1021/jp003919d
[42]	J. L. Banks, J. S. Beard, Y. Cao, A. E. Cho, W. Damm, R. Farid, A. K. Felts, T. A. Halgren, D. T. Mainz, J. R. Maple, R. Murphy, D. M. Philipp, M. P. Repasky, L. Y. Zhang, B. J. Berne, R. A. Friesner, E. Gallicchio and R. M. Levy, “Integrated Modeling Program, Applied Chemical Theory (IMPACT),” Journal of Computational Chemistry, Vol. 26, 2005, pp. 1752-1780. doi:10.1002/jcc.20292
[43]	R. Pauwels, J. Balzarini, M. Baba, R. Snoeck, D. Schols, P. Herdewijn, J. Desmyter and E. De Clercq, “Rapid and Automated Tetrazolium-Based Colorimetric Assay for the Detection of Anti-HIV Compounds,” Journal of Virological Methods, Vol. 20, No. 4, 1988, pp. 309-321. doi:10.1016/0166-0934(88)90134-6
[44]	M. Mihailescu and M. K. Gilson, “On the Theory of Noncovalent Binding,” Biophysical Journal, Vol. 87, No. 1, 2004, pp. 23-36. doi:10.1529/biophysj.103.031682
[45]	J. Kim and J. E. Straub, “Generalized Simulated Tempering for Exploring Strong Phase Transitions,” Journal of Chemical Physics, Vol. 133, No. 15, 2010, Article ID: 154101. doi:10.1063/1.3503503
[46]	D. H. Min, M. Chen, L. Q. Zheng, Y. H. Jin, M. A. Schwartz, Q.-X. A. Sang and W. Yang, “Enhancing qm/mm Molecular Dynamics Sampling in Explicit Environments via an Orthogonal-Space-Random-Walk-Based Strategy,” The Journal of Physical Chemistry B, Vol. 115, No. 14, 2011, pp. 3924-3935. doi:10.1021/jp109454q
[47]	C. A. Chang, W. Chen and M. K. Gilson, “Ligand Configurational Entropy and Protein Binding,” Proceedings of the National Academy of Sciences, Vol. 104, No. 5, 2007, pp. 1534-1539. doi:10.1073/pnas.0610494104