Expanding the Accessible Chemical Space of SIRT2 Inhibitors through Exploration of Binding Pocket Dynamics
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2022
Authors
Đoković, Nemanja
Ružić, Dušan

Rahnasto-Rilla, Mina
Srdić-Rajić, Tatjana

Lahtela-Kakkonen, Maija
Nikolić, Katarina

Article (Published version)

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Considerations of binding pocket dynamics are one of the crucial aspects of the rational design of binders. Identification of alternative conformational states or cryptic subpockets could lead to the discovery of completely novel groups of the ligands. However, experimental characterization of pocket dynamics, besides being expensive, may not be able to elucidate all of the conformational states relevant for drug discovery projects. In this study, we propose the protocol for computational simulations of sirtuin 2 (SIRT2) binding pocket dynamics and its integration into the structure-based virtual screening (SBVS) pipeline. Initially, unbiased molecular dynamics simulations of SIRT2:inhibitor complexes were performed using optimized force field parameters of SIRT2 inhibitors. Time-lagged independent component analysis (tICA) was used to design pocket-related collective variables (CVs) for enhanced sampling of SIRT2 pocket dynamics. Metadynamics simulations in the tICA eigenvector space ...revealed alternative conformational states of the SIRT2 binding pocket and the existence of a cryptic subpocket. Newly identified SIRT2 conformational states outperformed experimentally resolved states in retrospective SBVS validation. After performing prospective SBVS, compounds from the under-represented portions of the SIRT2 inhibitor chemical space were selected for in vitro evaluation. Two compounds, NDJ18 and NDJ85, were identified as potent and selective SIRT2 inhibitors, which validated the in silico protocol and opened up the possibility for generalization and broadening of its application. The anticancer effects of the most potent compound NDJ18 were examined on the triple-negative breast cancer cell line. Results indicated that NDJ18 represents a promising structure suitable for further evaluation.
Source:
Journal of Chemical Information and Modeling, 2022, 62, 10, 2571-2585Publisher:
- American Chemical Society
Funding / projects:
- Ministry of Education, Science and Technological Development, Republic of Serbia, Grant no. 200161 (University of Belgrade, Faculty of Pharmacy) (RS-200161)
- Modeling and Numerical Simulations of Complex Many-Body Systems (RS-171017)
- COST-Action CM1406 “Epigenetic Chemical Biology (EpiChemBio)”
DOI: 10.1021/acs.jcim.2c00241
ISSN: 1549-9596
WoS: 00080576220002
Scopus: 2-s2.0-85129263383
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PharmacyTY - JOUR AU - Đoković, Nemanja AU - Ružić, Dušan AU - Rahnasto-Rilla, Mina AU - Srdić-Rajić, Tatjana AU - Lahtela-Kakkonen, Maija AU - Nikolić, Katarina PY - 2022 UR - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4102 AB - Considerations of binding pocket dynamics are one of the crucial aspects of the rational design of binders. Identification of alternative conformational states or cryptic subpockets could lead to the discovery of completely novel groups of the ligands. However, experimental characterization of pocket dynamics, besides being expensive, may not be able to elucidate all of the conformational states relevant for drug discovery projects. In this study, we propose the protocol for computational simulations of sirtuin 2 (SIRT2) binding pocket dynamics and its integration into the structure-based virtual screening (SBVS) pipeline. Initially, unbiased molecular dynamics simulations of SIRT2:inhibitor complexes were performed using optimized force field parameters of SIRT2 inhibitors. Time-lagged independent component analysis (tICA) was used to design pocket-related collective variables (CVs) for enhanced sampling of SIRT2 pocket dynamics. Metadynamics simulations in the tICA eigenvector space revealed alternative conformational states of the SIRT2 binding pocket and the existence of a cryptic subpocket. Newly identified SIRT2 conformational states outperformed experimentally resolved states in retrospective SBVS validation. After performing prospective SBVS, compounds from the under-represented portions of the SIRT2 inhibitor chemical space were selected for in vitro evaluation. Two compounds, NDJ18 and NDJ85, were identified as potent and selective SIRT2 inhibitors, which validated the in silico protocol and opened up the possibility for generalization and broadening of its application. The anticancer effects of the most potent compound NDJ18 were examined on the triple-negative breast cancer cell line. Results indicated that NDJ18 represents a promising structure suitable for further evaluation. PB - American Chemical Society T2 - Journal of Chemical Information and Modeling T1 - Expanding the Accessible Chemical Space of SIRT2 Inhibitors through Exploration of Binding Pocket Dynamics VL - 62 IS - 10 SP - 2571 EP - 2585 DO - 10.1021/acs.jcim.2c00241 ER -
@article{ author = "Đoković, Nemanja and Ružić, Dušan and Rahnasto-Rilla, Mina and Srdić-Rajić, Tatjana and Lahtela-Kakkonen, Maija and Nikolić, Katarina", year = "2022", abstract = "Considerations of binding pocket dynamics are one of the crucial aspects of the rational design of binders. Identification of alternative conformational states or cryptic subpockets could lead to the discovery of completely novel groups of the ligands. However, experimental characterization of pocket dynamics, besides being expensive, may not be able to elucidate all of the conformational states relevant for drug discovery projects. In this study, we propose the protocol for computational simulations of sirtuin 2 (SIRT2) binding pocket dynamics and its integration into the structure-based virtual screening (SBVS) pipeline. Initially, unbiased molecular dynamics simulations of SIRT2:inhibitor complexes were performed using optimized force field parameters of SIRT2 inhibitors. Time-lagged independent component analysis (tICA) was used to design pocket-related collective variables (CVs) for enhanced sampling of SIRT2 pocket dynamics. Metadynamics simulations in the tICA eigenvector space revealed alternative conformational states of the SIRT2 binding pocket and the existence of a cryptic subpocket. Newly identified SIRT2 conformational states outperformed experimentally resolved states in retrospective SBVS validation. After performing prospective SBVS, compounds from the under-represented portions of the SIRT2 inhibitor chemical space were selected for in vitro evaluation. Two compounds, NDJ18 and NDJ85, were identified as potent and selective SIRT2 inhibitors, which validated the in silico protocol and opened up the possibility for generalization and broadening of its application. The anticancer effects of the most potent compound NDJ18 were examined on the triple-negative breast cancer cell line. Results indicated that NDJ18 represents a promising structure suitable for further evaluation.", publisher = "American Chemical Society", journal = "Journal of Chemical Information and Modeling", title = "Expanding the Accessible Chemical Space of SIRT2 Inhibitors through Exploration of Binding Pocket Dynamics", volume = "62", number = "10", pages = "2571-2585", doi = "10.1021/acs.jcim.2c00241" }
Đoković, N., Ružić, D., Rahnasto-Rilla, M., Srdić-Rajić, T., Lahtela-Kakkonen, M.,& Nikolić, K.. (2022). Expanding the Accessible Chemical Space of SIRT2 Inhibitors through Exploration of Binding Pocket Dynamics. in Journal of Chemical Information and Modeling American Chemical Society., 62(10), 2571-2585. https://doi.org/10.1021/acs.jcim.2c00241
Đoković N, Ružić D, Rahnasto-Rilla M, Srdić-Rajić T, Lahtela-Kakkonen M, Nikolić K. Expanding the Accessible Chemical Space of SIRT2 Inhibitors through Exploration of Binding Pocket Dynamics. in Journal of Chemical Information and Modeling. 2022;62(10):2571-2585. doi:10.1021/acs.jcim.2c00241 .
Đoković, Nemanja, Ružić, Dušan, Rahnasto-Rilla, Mina, Srdić-Rajić, Tatjana, Lahtela-Kakkonen, Maija, Nikolić, Katarina, "Expanding the Accessible Chemical Space of SIRT2 Inhibitors through Exploration of Binding Pocket Dynamics" in Journal of Chemical Information and Modeling, 62, no. 10 (2022):2571-2585, https://doi.org/10.1021/acs.jcim.2c00241 . .