Thermodynamic Behavior, Diffusion Mechanisms and Structural Properties of Panobinostat in Water
DOI:
https://doi.org/10.3126/jist.v30i2.84993Keywords:
HDACs inhibitors, Panobinostat,, Solvation Free Energy, Diffusion,, SASAAbstract
Panobinostat is used as a drug against multiple myeloma by inhibiting the enzymatic activity of HDAC enzymes. In this study, we have performed molecular dynamics simulation of Panobinostat in water at 310 K to investigate solvation free energy, diffusion mechanism and structural properties. TI, TI-CUBIC, BAR and MBAR have been used to estimate solvation free energy. Our findings indicate that Coulomb interaction is the dominant factor affecting solute solvation free energy. We have also investigated the solute-solvent interactions in terms of solvent accessible surface area (SASA) of solute molecule, and hydrogen bonds between the Panobinostat and water. Solute-solvent interaction revealed a mean SASA of 6.64 nm2 with an average of 6 hydrogen bonds between Panobinostat and water. The calculated self-diffusion coefficient of water agreed well with literature values within 4.26% deviation. Both bulk and shear viscosity significantly exceeded than pure water, indicating a viscous micro-environment around Panobinostat. Moreover, structural properties of the system have been analyzed using radial distribution function (RDF).
Downloads
References
Administration, F. a. D. (2014). FDA approves Beleodaq to treat rare, aggressive form of non-Hodgkin lymphoma. Retrieved October 20, 2014 from http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm403929.htm
Allen, M. P., & Tildesley, D. J. (2017). Computer simulation of liquids. Oxford university press.
Apol, E., Apostolov, R., Berendsen, H., Van Buuren, A., Bjelkmar, P., Van Drunen, R., Feenstra, A., Groenhof, G., Kasson, P., & Larsson, P. (2010). GROMACS user manual version 4.5. 4. Royal Institute of Technology and Uppsala University, Stockholm.
Bannan, C. C., Burley, K. H., Chiu, M., Shirts, M. R., Gilson, M. K., & Mobley, D. L. (2016). Blind prediction of cyclohexane–water distribution coefficients from the SAMPL5 challenge. Journal of computer-aided molecular design, 30(11), 927-944.
Berendsen, H. J., Postma, J. v., Van Gunsteren, W. F., DiNola, A., & Haak, J. R. (1984). Molecular dynamics with coupling to an external bath. The Journal of chemical physics, 81(8), 3684-3690.
Bhandari, D., & Adhikari, N. (2016). Molecular dynamics study of diffusion of krypton in water at different temperatures. International Journal of Modern Physics B, 30(11), 1650064.
Bhatta, T., Khanal, P., Khanal, S. P., & Adhikari, N. P. (2023). Thermodynamics and transport properties of valine and cysteine peptides in water. Journal of Molecular Liquids, 376, 121472.
Bobo, R. H., Laske, D. W., Akbasak, A., Morrison, P. F., Dedrick, R. L., & Oldfield, E. H. (1994). Convection-enhanced delivery of macromolecules in the brain. Proceedings of the National Academy of Sciences, 91(6), 2076-2080.
Bolden, J. E., Peart, M. J., & Johnstone, R. W. (2006). Anticancer activities of histone deacetylase inhibitors. Nature reviews Drug discovery, 5(9), 769-784.
Bussi, G., Donadio, D., & Parrinello, M. (2007). Canonical sampling through velocity rescaling. The Journal of Chemical Physics, 126(1).
Darken, L. (2010). Diffusion, mobility and their interrelation through free energy in binary metallic systems. Metallurgical materials transactions. B, Process Metallurgy Materials Processing Science, 41(2), 277-294.
De Vivo, M., Masetti, M., Bottegoni, G., & Cavalli, A. (2016). Role of molecular dynamics and related methods in drug discovery. Journal of Medicinal Chemistry, 59(9), 4035-4061.
Einstein, A. (1905). On the motion of small particles suspended in liquids at rest required by the molecular-kinetic theory of heat. Annalen der physik, 17(549-560), 208.
Geballe, M. T., Skillman, A. G., Nicholls, A., Guthrie, J. P., & Taylor, P. J. (2010). The SAMPL2 blind prediction challenge: introduction and overview. Journal of Computer-aided Molecular Design, 24(4), 259-279.
Georgalis, Y., Starikov, E., Hollenbach, B., Lurz, R., Scherzinger, E., Saenger, W., Lehrach, H., & Wanker, E. E. (1998). Huntingtin aggregation monitored by dynamic light scattering. Proceedings of the National Academy of Sciences, 95(11), 6118-6121.
Giles, F., Fischer, T., Cortes, J., Garcia-Manero, G., Beck, J., Ravandi, F., Masson, E., Rae, P., Laird, G., & Sharma, S. (2006). A phase I study of intravenous LBH589, a novel cinnamic hydroxamic acid analogue histone deacetylase inhibitor, in patients with refractory hematologic malignancies. Clinical Cancer Research, 12(15), 4628-4635.
Gill, T., Barua, N., Woolley, M., Bienemann, A., Johnson, D., Murray, G., Fennelly, C., Lewis, O., Irving, C., & Wyatt, M. (2013). In vitro and in vivo testing of a novel recessed-step catheter for reflux-free convection-enhanced drug delivery to the brain. Journal of Neuroscience Methods, 219(1), 1-9.
Gromiha, M. M., & Ahmad, S. (2005). Role of solvent accessibility in structure based drug design. Current Computer-Aided Drug Design, 1(3), 223-235.
Gryder, B. E., Sodji, Q. H., & Oyelere, A. K. (2012). Targeted cancer therapy: giving histone deacetylase inhibitors all they need to succeed. Future Medicinal Chemistry, 4(4), 505-524.
Guthrie, J. P. (2009). A blind challenge for computational solvation free energies: introduction and overview. The Journal of Physical Chemistry B, 113(14), 4501-4507.
Hess, B. (2002). Determining the shear viscosity of model liquids from molecular dynamics simulations. The Journal of Chemical Physics, 116(1), 209-217.
Hess, B., Bekker, H., Berendsen, H. J., & Fraaije, J. G. (1997). LINCS: A linear constraint solver for molecular simulations. Journal of Computational Chemistry, 18(12), 1463-1472.
Homan, M. J., Franson, A., Ravi, K., Roberts, H., Pai, M. P., Liu, C., He, M., Matvekas, A., Koschmann, C., & Marini, B. L. (2021). Panobinostat penetrates the blood–brain barrier and achieves effective brain concentrations in a murine model. Cancer Chemotherapy Pharmacology, 88(3), 555-562.
Huang, J., Rauscher, S., Nawrocki, G., Ran, T., Feig, M., de Groot, B. L., Grubmuller, H., & MacKerell, A. D., Jr. (2017, Jan). CHARMM36m: an improved force field for folded and intrinsically disordered proteins. Nature Methods, 14(1), 71-73. https://doi.org/10.1038/nmeth.4067
Humphrey, W., Dalke, A., & Schulten, K. J. (1996). VMD: visual molecular dynamics. 14(1), 33-38.
Jiang, X.-J., Huang, K.-K., Yang, M., Qiao, L., Wang, Q., Ye, J.-Y., Zhou, H.-S., Yi, Z.-S., Wu, F.-Q., & Wang, Z.-X. (2012). Synergistic effect of panobinostat and bortezomib on chemoresistant acute myelogenous leukemia cells via AKT and NF-κB pathways. Cancer Letert, 326(2), 135-142.
Jones, S. F., Bendell, J. C., Infante, J. R., Spigel, D. R., Thompson, D. S., Yardley, D. A., Greco, F. A., Murphy, P. B., & Burris 3rd, H. A. (2011). A phase I study of panobinostat in combination with gemcitabine in the treatment of solid tumors. Clin Adv Hematol Oncol, 9(3), 225-230.
Karplus, M., & Petsko, G. A. (1990). Molecular dynamics simulations in biology. Nature, 347(6294), 631-639.
Khanal, S. P., & Adhikari, N. P. (2022). Thermodynamic and transport properties of amoxicillin. Journal of Molecular Liquids, 354, 118865.
Khanal, S. P., Kandel, Y. P., & Adhikari, N. P. (2019). Transport properties of zwitterion glycine, diglycine, and triglycine in water. AIP advances, 9, 065303
Kim, S., Chen, J., Cheng, T., Gindulyte, A., He, J., He, S., Li, Q., Shoemaker, B. A., Thiessen, P. A., & Yu, B. (2025). PubChem 2025 update. Nucleic Acids Research, 53(D1), D1516-D1525.
Knox, C., Wilson, M., Klinger, C. M., Franklin, M., Oler, E., Wilson, A., Pon, A., Cox, J., Chin, N. E., & Strawbridge, S. A. (2024). DrugBank 6.0: the DrugBank knowledgebase for 2024. Nucleic Acids Research, 52(D1), D1265-D1275.
Kraml, J., Kamenik, A. S., Waibl, F., & Schauperl, M. (2019). Solvation free energy as a measure of hydrophobicity: application to serine protease binding interfaces. Journal of Chemical Theory Computation, 15(11), 5872-5882.
Krewson, C. E., & Saltzman, W. M. (1996). Transport and elimination of recombinant human NGF during long-term delivery to the brain. Brain research, 727(1-2), 169-181.
Kusaczuk, M., Krętowski, R., Stypułkowska, A., & Cechowska-Pasko, M. (2016). Molecular and cellular effects of a novel hydroxamate-based HDAC inhibitor–belinostat–in glioblastoma cell lines: a preliminary report. Investigational New Drugs, 34(5), 552-564.
Lee, J., Cheng, X., Swails, J. M., Yeom, M. S., Eastman, P. K., Lemkul, J. A., Wei, S., Buckner, J., Jeong, J. C., Qi, Y., Jo, S., Pande, V. S., Case, D. A., Brooks, C. L., 3rd, MacKerell, A. D., Jr., Klauda, J. B., & Im, W. (2016). CHARMM-GUI Input Generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM/OpenMM Simulations Using the CHARMM36 Additive Force Field. Journal of Chemical Theory Computation, 12(1), 405-413. https://doi.org/10.1021/acs.jctc.5b00935
Liu, S., Cao, S., Hoang, K., Young, K. L., Paluch, A. S., & Mobley, D. L. (2016). Using MD simulations to calculate how solvents modulate solubility. Journal of Chemical Theory Computation, 12(4), 1930-1941.
Maginn, E. J., Messerly, R. A., Carlson, D. J., Roe, D. R., & Elliot, J. R. (2019). Best practices for computing transport properties 1. Self-diffusivity and viscosity from equilibrium molecular dynamics Living Journal of Computational Molecular Science, 1(1), 6324-6324.
Morabito, F., Voso, M. T., Hohaus, S., Gentile, M., Vigna, E., Recchia, A. G., Iovino, L., Benedetti, E., Lo-Coco, F., & Galimberti, S. (2016). Panobinostat for the treatment of acute myelogenous leukemia. Expert Opinion on Investigational Drugs, 25(9), 1117-1131.
Morrison, P. F., Laske, D. W., Bobo, H., Oldfield, E. H., & Dedrick, R. L. (1994). High-flow microinfusion: tissue penetration and pharmacodynamics. American Journal of Physiology-Regulatory, Integrative Comparative Physiology, 266(1), R292-R305.
Pan, D., Mouhieddine, T. H., Upadhyay, R., Casasanta, N., Lee, A., Zubizarreta, N., Moshier, E., & Richter, J. (2023). Outcomes with panobinostat in heavily pretreated multiple myeloma patients. Seminars in oncology,
Parrinello, M., & Rahman, A. (1981). Polymorphic transitions in single crystals: A new molecular dynamics method. Journal of Applied Physics, 52(12), 7182-7190.
Pettersen, E. F., Goddard, T. D., Huang, C. C., Meng, E. C., Couch, G. S., Croll, T. I., Morris, J. H., & Ferrin, T. E. J. P. S. (2021). UCSF ChimeraX: Structure visualization for researchers, educators, and developers. 30(1), 70-82.
Raedler, L. A. (2016). Farydak (Panobinostat): first HDAC inhibitor approved for patients with relapsed multiple myeloma. American health drug benefits, 9(Spec Feature), 84.
Rah, K., & Eu, B. C. (1999). Relation of shear viscosity and self-diffusion coefficient for simple liquids. Physical Review E, 60(4), 4105.
Rajak, H., Singh, A., Raghuwanshi, K., Kumar, R., Dewangan, P., Veerasamy, R., Sharma, P., Dixit, A., & Mishra, P. (2014). A structural insight into hydroxamic acid based histone deacetylase inhibitors for the presence of anticancer activity. Current Medicinal Chemistry, 21(23), 2642-2664.
Rapaport, D. C. (2004). The art of molecular dynamics simulation. Cambridge university press.
Rodgers, L. T., Lester McCully, C. M., Odabas, A., Cruz, R., Peer, C. J., Figg, W. D., & Warren, K. E. (2020). Characterizing the pharmacokinetics of panobinostat in a non-human primate model for the treatment of diffuse intrinsic pontine glioma. Cancer Chemotherapy Pharmacology, 85(4), 827-830.
Rosas Jiménez, J. G., Fábián, B., & Hummer, G. (2024). Faster Sampling in Molecular Dynamics Simulations with TIP3P-F Water. Journal of Chemical Theory Computation, 20(24), 11068-11081.
San José-Enériz, E., Gimenez-Camino, N., Agirre, X., & Prosper, F. (2019). HDAC inhibitors in acute myeloid leukemia. Cancers, 11(11), 1794.
Shirts, M. R., & Chodera, J. D. (2008). Statistically optimal analysis of samples from multiple equilibrium states. The Journal of Chemical Physics, 129, 124105.
Shirts, M. R., Mobley, D. L., & Chodera, J. D. (2007). Alchemical free energy calculations: ready for prime time? Annual Reports in Computational Chemistry, 3, 41-59.
Shirts, M. R., & Pande, V. S. (2005). Comparison of efficiency and bias of free energies computed by exponential averaging, the Bennett acceptance ratio, and thermodynamic integration. The Journal of Chemical Physics, 122, 144107.
Sivaraj, D., Green, M. M., & Gasparetto, C. (2016). Panobinostat for the management of multiple myeloma. Future oncology, 13(6), 477-488.
Tsai, P., Wu, G., Baker, C. E., Thayer, W. O., Spagnuolo, R. A., Sanchez, R., Barrett, S., Howell, B., Margolis, D., & Hazuda, D. (2016). In vivo analysis of the effect of panobinostat on cell-associated HIV RNA and DNA levels and latent HIV infection. Retrovirology, 13(1), 36.
Tuckerman, M. E. (2023). Statistical mechanics: theory and molecular simulation. Oxford university press.
Van Der Spoel, D., Lindahl, E., Hess, B., Groenhof, G., Mark, A. E., & Berendsen, H. J. (2005). GROMACS: fast, flexible, and free. Journal of Computational Chemistry, 26(16), 1701-1718.
Wu, D., & Kofke, D. A. (2005). Phase-space overlap measures. II. Design and implementation of staging methods for free-energy calculations. The Journal of Chemical Physics, 123, 084109.
Zwanzig, R. W. (1954). High‐temperature equation of state by a perturbation method. I. Nonpolar gases. The Journal of Chemical Physics, 22(8), 1420-1426.
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2025 Institute of Science and Technology, T.U.
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
The views and interpretations in this journal are those of the author(s). They are not attributable to the Institute of Science and Technology, T.U. and do not imply the expression of any opinion concerning the legal status of any country, territory, city, area of its authorities, or concerning the delimitation of its frontiers of boundaries.
The copyright of the articles is held by the Institute of Science and Technology, T.U.
