MOLECULAR DYNAMICS EXAMINATION OF THE CRYPTIC SUBPOCKET OF SIRTUIN 2

17th International Conference on Fundamental and Applied Aspects of Physical Chemistry (Proceedings, Volume II) (2024) [O-14-P, pp. 639-642]   

AUTHOR(S) / АУТОР(И): Nemanja Đoković , V. Marković and Katarina Nikolić

Download Full Pdf   

DOI: 10.46793/Phys.Chem24II.639DJ

ABSTRACT / САЖЕТАК:

Recently described alternative conformational state of sirtuin 2 (SIRT2) characterized by a cryptic subpocket paved the way for this study which investigates the significance of the newly identified cryptic subpocket in designing a group of SIRT2 inhibitors, derivatives of 4-(4- pyridylmethyl)aniline. With this aim, molecular dynamics simulations were conducted, initiating from two distinct conformational states of SIRT2 defined by the absence, or presence of the cryptic subpocket. Based on the analysis of the generated trajectories and estimated free energies of binding for reference and designed inhibitor, it has been shown that studied ligands were able to stabilize protein in both conformational states. Furthermore, the results suggest that the further design of novel 4-(4-pyridylmethyl)anilines could be focused on finding optimal substitution pattern to facilitate interactions with residue Phe132 within the cryptic subpocket.

KEYWORDS / КЉУЧНЕ РЕЧИ:

ACKNOWLEDGEMENT / ПРОЈЕКАТ:

This research was funded by the Ministry of Science, Technological Development and Innovation, Republic of Serbia through two Grant Agreements with University of Belgrade-Faculty of Pharmacy No 451-03-65/2024-03/200161 and No 451-03-66/2024-03/200161. The authors thank the COST Actions CA18240, CA18133 and CA22125 of the European Community for support.

REFERENCES / ЛИТЕРАТУРА:

  • H. Dai, D. A. Sinclair, J. L. Ellis, C. Steegborn, Pharmacol. Ther., 188 (2018) 140.
  • Ri. Machado de Oliveira, J. Sarkander, A. Kazantsev, T. Outeiro, Front. Pharmacol. 2012, 3.
  • N. Djokovic, D. Ruzic, M. Rahnasto-Rilla, T. Srdic-Rajic, M. Lahtela-Kakkonen, K. Nikolic, J. Chem. Inf. Model., 62 (2022) 2571.
  • M. J. Abraham, T. Murtola, R. Schulz, S. Páll, J. C. Smith, B. Hess, E. Lindahl, SoftwareX, 1–2 (2015) 19.
  • J. Huang, A. D. MacKerell, J. Comput. Chem., 34 (2013) 2135.
  • K. Vanommeslaeghe, A. D. MacKerell, J. Chem. Inf. Model., 52 (2012) 3144.
  • G. Jones, P. Willett, R. C. Glen, A. R. Leach, R. Taylor, J. Mol. Biol., 267 (1997) 727.
  • O. Korb, T. Stützle, T. E. Exner, J. Chem. Inf. Model., 49 (2009) 84.
  • M. S. Valdés-Tresanco, M. E. Valdés-Tresanco, P. A. Valiente, E. Moreno, J. Chem. Theory Comput., 17 (2021) 6281.