Revolutionizing Drug Targeting Strategies: Integrating Artificial Intelligence and Structure-Based Methods in PROTAC Development
Abstract
1. Introduction
2. PROTAC Advancement
3. PROTAC Advantages
4. PROTAC Disadvantages
5. E3 ligases in PROTAC
6. Linker in PROTAC
7. PROTAC Design Strategies
8. PROTAC Development Using Structure-Based Approaches
9. PROTAC Development Using Machine Learning
Model | Method | Description | Ref |
---|---|---|---|
Zheng S. et al. | Deep reinforcement learning in combination with machine learning-based classifiers and MD simulations. |
| [89] |
DeepPROTACs | Graph Convolutional Networks. |
| [90] |
Nori D. et al. | Graph-based generative models and reinforcement learning. |
| [91] |
MAPD | Naïve Bayes, KNN, LR LiblineaR, SVMLinear, SVMRadial, and Random Forest. |
| [92] |
Poongavanam V. et al. | Random Forest, Decision Tree, Support Vector Machine, and Kappa Nearest Neighbor. |
| [93] |
10. Conclusions and Future Direction
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Burslem, G.M.; Crews, C.M. Proteolysis-Targeting Chimeras as Therapeutics and Tools for Biological Discovery. Cell 2020, 181, 102–114. [Google Scholar] [CrossRef]
- Zou, Y.; Ma, D.; Wang, Y. The PROTAC technology in drug development. Cell Biochem. Funct. 2019, 37, 21–30. [Google Scholar] [CrossRef] [PubMed]
- Békés, M.; Langley, D.R.; Crews, C.M. PROTAC targeted protein degraders: The past is prologue. Nat. Rev. Drug. Discov. 2022, 21, 181–200. [Google Scholar] [CrossRef] [PubMed]
- Bond, M.J.; Crews, C.M. Proteolysis targeting chimeras (PROTACs) come of age: Entering the third decade of targeted protein degradation. RSC Chem. Biol. 2021, 2, 725–742. [Google Scholar] [CrossRef] [PubMed]
- Zhao, L.; Zhao, J.; Zhong, K.; Tong, A.; Jia, D. Targeted protein degradation: Mechanisms, strategies and application. Sig. Transduct. Target. Ther. 2022, 7, 113. [Google Scholar] [CrossRef] [PubMed]
- Pei, H.; Peng, Y.; Zhao, Q.; Chen, Y. Small molecule PROTACs: An emerging technology for targeted therapy in drug discovery. RSC Adv. 2019, 9, 16967–16976. [Google Scholar] [CrossRef]
- Burke, M.R.; Smith, A.R.; Zheng, G. Overcoming Cancer Drug Resistance Utilizing PROTAC Technology. Front. Cell Dev. Biol. 2022, 10, 872729. [Google Scholar] [CrossRef] [PubMed]
- He, M.; Cao, C.; Ni, Z.; Liu, Y.; Song, P.; Hao, S.; He, Y.; Sun, X.; Rao, Y. PROTACs: Great opportunities for academia and industry (an update from 2020 to 2021). Sig. Transduct. Target. Ther. 2022, 7, 181. [Google Scholar] [CrossRef]
- Hu, Z.; Crews, C.M. Recent Developments in PROTAC-Mediated Protein Degradation: From Bench to Clinic. ChemBioChem 2022, 23, e202100270. [Google Scholar] [CrossRef]
- Qi, S.M.; Dong, J.; Xu, Z.Y.; Cheng, X.D.; Zhang, W.D.; Qin, J.J. (PROTAC: An Effective Targeted Protein Degradation Strategy for Cancer Therapy. Front. Pharmacol. 2021, 12, 692574. [Google Scholar] [CrossRef]
- Sakamoto, K.M.; Kim, K.B.; Kumagai, A.; Mercurio, F.; Crews, C.M.; Deshaies, R.J. PROTACS: Chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proc. Natl. Acad. Sci. USA 2001, 98, 8554–8559. [Google Scholar] [CrossRef]
- Xie, H.; Liu, J.; Alem Glison, D.M.; Fleming, J.B. The clinical advances of proteolysis targeting chimeras in oncology. Explor. Target. Antitumor. Ther. 2021, 6, 511–521. [Google Scholar] [CrossRef]
- Kelm, J.M.; Pandey, D.S.; Malin, E.; Kansou, H.; Arora, S.; Kumar, R.; Gavande, N.S. PROTAC’ing oncoproteins: Targeted protein degradation for cancer therapy. Mol. Cancer 2023, 22, 62. [Google Scholar] [CrossRef]
- Weng, G.; Shen, C.; Cao, D.; Gao, J.; Dong, X.; He, Q.; Yang, B.; Li, D.; Wu, J.; Hou, T. PROTAC-DB: An online database of PROTACs. Nucleic Acids Res. 2021, 49, D1381–D1387. [Google Scholar] [CrossRef]
- Weng, G.; Cai, X.; Cao, D.; Du, H.; Shen, C.; Deng, Y.; He, Q.; Yang, B.; Li, D.; Hou, T. PROTAC-DB 2.0: An updated database of PROTACs. Nucleic Acids Res. 2023, 6, D1367–D1372. [Google Scholar] [CrossRef] [PubMed]
- Kim, H.; Park, J.; Kim, J.M. Targeted Protein Degradation to Overcome Resistance in Cancer Therapies: PROTAC and N-Degron Pathway. Biomedicines 2022, 10, 2100. [Google Scholar] [CrossRef]
- Liu, Z.; Hu, M.; Yang, Y.; Du, C.; Zhou, H.; Liu, C.; Chen, Y.; Fan, L.; Ma, H.; Gong, Y.; et al. An overview of PROTACs: A promising drug discovery paradigm. Mol. Biomed. 2022, 3, 46. [Google Scholar] [CrossRef]
- Martín, P.A.; Xiao, X. PROTACs to address the challenges facing small molecule inhibitors. Eur. J. Med. Chem. 2021, 210, 112993. [Google Scholar] [CrossRef]
- Kannt, A.; Đikić, I. Expanding the arsenal of E3 ubiquitin ligases for proximity-induced protein degradation. Cell Chem. Biol. 2021, 28, 1014–1031. [Google Scholar] [CrossRef]
- Liu, Y.; Yang, J.; Wang, T.; Luo, M.; Chen, Y.; Chen, C.; Ronai, Z.; Zhou, Y.; Ruppin, E.; Han, L. Expanding PROTACtable genome universe of E3 ligases. Nat. Commun. 2023, 14, 6509. [Google Scholar] [CrossRef]
- Ishida, T.; Ciulli, A. E3 Ligase Ligands for PROTACs: How They Were Found and How to Discover New Ones. SLAS Discov. 2021, 26, 484–502. [Google Scholar] [CrossRef]
- Belcher, B.P.; Ward, C.C.; Nomura, D.K. Ligandability of E3 Ligases for Targeted Protein Degradation Applications. Biochemistry. 2023, 62, 588–600. [Google Scholar] [CrossRef]
- Sampson, C.; Wang, Q.; Otkur, W.; Zhao, H.; Lu, Y.; Liu, X.; Piao, H.L. The roles of E3 ubiquitin ligases in cancer progression and targeted therapy. Clin. Transl. Med. 2023, 13, e1204. [Google Scholar] [CrossRef]
- Yang, Q.; Zhao, J.; Chen, D.; Wang, Y. E3 ubiquitin ligases: Styles, structures and functions. Mol. Biomed. 2021, 2, 23. [Google Scholar] [CrossRef] [PubMed]
- Humphreys, L.M.; Smith, P.; Chen, Z.; Fouad, S.; D’Angiolella, V. The role of E3 ubiquitin ligases in the development and progression of glioblastoma. Cell Death Differ. 2021, 28, 522–537. [Google Scholar] [CrossRef] [PubMed]
- Diehl, C.J.; Ciulli, A. Discovery of small molecule ligands for the von Hippel-Lindau (VHL) E3 ligase and their use as inhibitors and PROTAC degraders. Chem. Soc. Rev. 2022, 51, 8216–8257. [Google Scholar] [CrossRef] [PubMed]
- Michaelides, I.N.; Collie, G.W. E3 Ligases Meet Their Match: Fragment-Based Approaches to Discover New E3 Ligands and to Unravel E3 Biology. J. Med. Chem. 2023, 66, 3173–3194. [Google Scholar] [CrossRef]
- Wang, G.; Chan, C.H.; Gao, Y.; Lin, H.K. Novel roles of Skp2 E3 ligase in cellular senescence, cancer progression, and metastasis. Chin. J. Cancer 2012, 31, 169–177. [Google Scholar] [CrossRef]
- Chan, C.H.; Morrow, J.K.; Li, C.F.; Gao, Y.; Jin, G.; Moten, A.; Stagg, L.J.; Ladbury, J.E.; Cai, Z.; Xu, D.; et al. Pharmacological inactivation of Skp2 SCF ubiquitin ligase restricts cancer stem cell traits and cancer progression. Cell 2013, 154, 556–568. [Google Scholar] [CrossRef] [PubMed]
- Ohoka, N.; Tsuji, G.; Shoda, T.; Fujisato, T.; Kurihara, M.; Demizu, Y.; Naito, M. Development of Small Molecule Chimeras That Recruit AhR E3 Ligase to Target Proteins. ACS Chem. Biol. 2019, 14, 2822–2832. [Google Scholar] [CrossRef]
- Li, L.; Mi, D.; Pei, H.; Duan, Q.; Wang, X.; Zhou, W.; Jin, J.; Li, D.; Liu, M.; Chen, Y. In vivo target protein degradation induced by PROTACs based on E3 ligase DCAF15. Signal. Transduct. Target. Ther. 2020, 5, 129. [Google Scholar] [CrossRef]
- Karki, R.; Gadiya, Y.; Gribbon, P.; Zaliani, A. Pharmacophore-Based Machine Learning Model To Predict Ligand Selectivity for E3 Ligase Binders. ACS Omega 2023, 8, 30177–30185. [Google Scholar] [CrossRef]
- Collins, K.H.; Winter, G.E.; Bernardes, G.L. The role of reversible and irreversible covalent chemistry in targeted protein. Cell Chem. Biol. 2021, 28, 952–968. [Google Scholar] [CrossRef] [PubMed]
- Ward, C.C.; Kleinman, J.I.; Brittain, S.M.; Lee, P.S.; Chung, C.Y.S.; Kim, K.; Petri, Y.; Thomas, J.R.; Tallarico, J.A.; McKenna, J.M.; et al. Covalent Ligand Screening Uncovers a RNF4 E3 Ligase Recruiter for Targeted Protein Degradation Applications. ACS Chem. Biol. 2019, 14, 2430–2440. [Google Scholar] [CrossRef]
- Henning, N.J.; Manford, A.G.; Spradlin, J.N.; Brittain, S.M. Discovery of a Covalent FEM1B Recruiter for Targeted Protein Degradation Applications. J. Am. Chem. Soc. 2022, 144, 701–708. [Google Scholar] [CrossRef]
- Pinch, B.J.; Buckley, D.L.; Gleim, S.; Brittain, S.M.; Tandeske, L.; D’Alessandro, P.L.; Hauseman, Z.J.; Lipps, J.; Xu, L.; Harvey, E.P.; et al. A strategy to assess the cellular activity of E3 ligase components against neo-substrates using electrophilic probes. Cell Chem. Biol. 2022, 29, 57–66. [Google Scholar] [CrossRef]
- Haque, A.; Engel, J.; Teichmann, S.A.; Lönnberg, T.A. A practical guide to single-cell RNA-sequencing for biomedical research and clinical applications. Genome Med. 2017, 9, 75. [Google Scholar] [CrossRef] [PubMed]
- Jovic, D.; Liang, X.; Zeng, H.; Lin, L.; Xu, F.; Luo, Y. Single-cell RNA sequencing technologies and applications: A brief overview. Clin. Transl. Med. 2022, 12, e694. [Google Scholar] [CrossRef]
- Hoch, M.; Rauthe, J.; Cesnulevicius, K.; Schultz, M.; Lescheid, D.; Wolkenhauer, O.; Chiurchiù, V.; Gupta, S. Cell-Type-Specific Gene Regulatory Networks of Pro-Inflammatory and Pro-Resolving Lipid Mediator Biosynthesis in the Immune System. Int. J. Mol. Sci. 2023, 24, 4342. [Google Scholar] [CrossRef]
- Ding, S.; Chen, X.; Shen, K. Single-cell RNA sequencing in breast cancer: Understanding tumor heterogeneity and paving roads to individualized therapy. Cancer Commun. 2020, 40, 329–344. [Google Scholar] [CrossRef] [PubMed]
- He, Y.; Khan, S.; Huo, Z.; Lv, D.; Zhang, X.; Liu, X.; Yuan, Y.; Hromas, R.; Xu, M.; Zheng, G.; et al. Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies. J. Hematol. Oncol. 2020, 13, 103. [Google Scholar] [CrossRef] [PubMed]
- Kaneko, M.; Iwase, I.; Yamasaki, Y.; Takai, T.; Wu, Y.; Kanemoto, S.; Matsuhisa, K.; Asada, R.; Okuma, Y.; Watanabe, T.; et al. Genome-wide identification and gene expression profiling of ubiquitin ligases for endoplasmic reticulum protein degradation. Sci. Rep. 2016, 6, 30955. [Google Scholar] [CrossRef] [PubMed]
- Lin, K.; Shen, S.H.; Lu, F.; Zheng, P.; Wu, S.; Liao, J.; Jiang, X.; Zeng, G.; Wei, D. CRISPR screening of E3 ubiquitin ligases reveals Ring Finger Protein 185 as a novel tumor suppressor in glioblastoma repressed by promoter hypermethylation and miR-587. J. Transl. Med. 2022, 20, 96. [Google Scholar] [CrossRef]
- Bock, C.; Datlinger, P.; Chardon, F.; Coelho, M.A.; Dong, M.B.; Lawson, K.A.; Lu, T.; Maroc, L.; Norman, T.M.; Song, B.; et al. High-content CRISPR screening. Nat. Rev. Methods Primers 2022, 2, 8. [Google Scholar] [CrossRef]
- Medvar, B.; Raghuram, V.; Pisitkun, T.; Sarka, A.; Knepper, M.A. Comprehensive database of human E3 ubiquitin ligases: Application to aquaporin-2 regulation. Physiol. Genom. 2016, 48, 502–512. [Google Scholar] [CrossRef] [PubMed]
- Park, S.; Khan, S.; Wahab, A. E3-targetpred: Prediction of e3-target proteins using deep latent space encoding. arXiv 2020, arXiv:2007.12073. [Google Scholar]
- Palomba, T.; Baroni, M.; Cross, S.; Cruciani, G.; Siragusa, L. ELIOT: A platform to navigate the E3 pocketome and aid the design of new PROTACs. Chem. Biol. Drug Des. 2023, 101, 69–86. [Google Scholar] [CrossRef]
- Hanzl, A.; Casement, R.; Imrichova, H.; Hughes, S.J.; Barone, E.; Testa, A.; Bauer, S.; Wright, J.; Brand, M.; Ciulli, A.; et al. Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders. Nat. Chem. Biol. 2023, 19, 323–333. [Google Scholar] [CrossRef]
- Li, K.; Crews, C.M. PROTACs: Past, present and future. Chem. Soc. Rev. 2022, 51, 5214–5236. [Google Scholar] [CrossRef]
- Bemis, T.A.; La Clair, J.J.; Burkart, M.D. Unraveling the Role of Linker Design in Proteolysis Targeting Chimeras. J. Med. Chem. 2021, 64, 8042–8052. [Google Scholar] [CrossRef]
- Cecchini, C.; Pannilunghi, S.; Tardy, S.; Scapozza, L. From Conception to Development: Investigating PROTACs Features for Improved Cell Permeability and Successful Protein Degradation. Front. Chem. 2021, 9, 672267. [Google Scholar] [CrossRef] [PubMed]
- Cyrus, K.; Wehenkel, M.; Choi, E.Y.; Han, H.J.; Lee, H.; Swanson, H.; Kim, K.B. Impact of linker length on the activity of PROTACs. Mol. Biosyst. 2011, 7, 359–364. [Google Scholar] [CrossRef] [PubMed]
- Farnaby, W.; Koegl, M.; Roy, M.J.; Whitworth, C.; Diers, E.; Trainor, N.; Zollman, D.; Steurer, S.; Karolyi-Oezguer, J.; Riedmueller, C.; et al. BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design. Nat. Chem. Biol 2019, 15, 672–680. [Google Scholar] [CrossRef] [PubMed]
- Han, X.; Wang, C.; Qin, C.; Xiang, W.; Fernandez-Salas, E.; Yang, C.Y.; Wang, M.; Zhao, L.; Xu, T.; Chinnaswamy, K.; et al. Discovery of ARD-69 as a highly potent proteolysis targeting chimera (PROTAC) degrader of Androgen Receptor (AR) for the treatment of prostate cancer. J. Med. Chem. 2019, 62, 941–964. [Google Scholar] [CrossRef] [PubMed]
- Desantis, J.; Mammoli, A.; Eleuteri, M.; Coletti, A.; Croci, F.; Macchiarulo, A.; Goracci, L. PROTACs bearing piperazine-containing linkers: What effect on their protonation state? RSC. Adv. 2022, 12, 21968–21977. [Google Scholar] [CrossRef]
- Burslem, G.M.; Smith, B.E.; Lai, A.C.; Jaime-Figueroa, S.; McQuaid, D.C.; Bondeson, D.P.; Toure, M.; Dong, H.; Qian, Y.; Wang, J.; et al. The advantages of targeted protein degradation over inhibition: An RTK case study. Cell Chem. Biol. 2018, 25, 67–77.e63. [Google Scholar] [CrossRef] [PubMed]
- Nowak, R.P.; DeAngelo, S.L.; Buckley, D.; He, Z.; Donovan, K.A.; An, J.; Safaee, N.; Jedrychowski, M.P.; Ponthier, C.M.; Ishoey, M.; et al. Plasticity in binding confers selectivity in ligand-induced protein degradation. Nat. Chem. Biol. 2018, 14, 706–714. [Google Scholar] [CrossRef] [PubMed]
- Bricelj, A.; Steinebach, C.; Kuchta, R.; Gütschow, M.; Sosič, I. E3 Ligase Ligands in Successful PROTACs: An Overview of Syntheses and Linker Attachment Points. Front. Chem. 2021, 9, 707317. [Google Scholar] [CrossRef]
- Bian, J.; Ren, J.; Li, Y.; Wang, J.; Xu, X.; Feng, Y.; Tang, H.; Wang, Y.; Li, Z. Discovery of Wogonin-based PROTACs against CDK9 and capable of achieving antitumor activity. Bioorg. Chem. 2018, 81, 373–381. [Google Scholar] [CrossRef]
- Imrie, F.; Bradley, A.R.; van der Schaar, M.; Deane, C.M. Deep Generative Models for 3D Linker Design. J. Chem. Inf. Model. 2020, 60, 1983–1995. [Google Scholar] [CrossRef]
- Guo, J.; Knuth, F.; Margreitter, C.; Janet, J.P.; Papadopoulos, K.; Engkvist, O.; Patronov, A. Link-INVENT: Generative Linker Design with Reinforcement Learning. Digit. Discov. 2023, 2, 392–408. [Google Scholar] [CrossRef]
- Kao, T.C.; Lin, T.C.; Chou, L.C.; Lin, C.C. Fragment Linker Prediction Using Deep Encoder-Decoder Network for PROTAC Drug Design. J. Chem. Inf. Model. 2023, 63, 2918–2927. [Google Scholar] [CrossRef]
- Tan, Y.; Dai, L.; Huang, W.; Guo, Y.; Zheng, S. DRlinker: Deep Reinforcement Learning for Optimization in Fragment Linking Design. J. Chem. Inf. Model. 2022, 62, 5907–5917. [Google Scholar] [CrossRef]
- Neeser, R.M.; Akdel, M.; Kovtun, D.; Naef, L. Reinforcement Learning-Driven Linker Design via Fast Attention-based Point Cloud Alignment. arXiv 2023, arXiv:2306.08166. [Google Scholar]
- Li, B.; Ran, T.; Chen, H. 3D Based Generative PROTAC Linker Design with Reinforcement Learning. Brief. Bioinform. 2023, 24, bbad323. [Google Scholar] [CrossRef]
- Smith, B.E.; Wang, S.L.; Figueroa, J.S.; Harbin, A.; Wang, J.; Hamman, B.D.; Crews, C.M. Differential PROTAC substrate specificity dictated by orientation of recruited E3 ligase. Nat. Commun. 2019, 10, 131. [Google Scholar] [CrossRef]
- Bondeson, D.P.; Smith, B.E.; Burslem, G.M.; Buhimschi, A.D.; Hines, J.; Jaime-Figueroa, S.; Wang, J.; Hamman, B.D.; Ishchenko, A.; Crews, C.M. Lessons in PROTAC design from selective degradation with a promiscuous warhead. Cell Chem. Biol. 2018, 25, 78–87.e5. [Google Scholar] [CrossRef]
- Němec, V.; Schwalm, M.P.; Müller, S.; Knapp, S. PROTAC degraders as chemical probes for studying target biology and target validation. Chem. Soc. Rev. 2022, 51, 7971–7993. [Google Scholar] [CrossRef]
- Samarasinghe, K.T.G.; Crews, C.M. Targeted protein degradation: A promise for undruggable proteins. Cell Chem. Biol. 2021, 28, 934–951. [Google Scholar] [CrossRef]
- Salama, A.K.A.A.; Trkulja, M.V.; Casanova, E.; Uras, I.Z. Targeted Protein Degradation: Clinical Advances in the Field of Oncology. Int. J. Mol. Sci. 2022, 23, 15440. [Google Scholar] [CrossRef]
- He, S.; Dong, G.; Cheng, J.; Wu, Y.; Sheng, C. Strategies for designing proteolysis targeting chimaeras (PROTACs). Med. Res. Rev. 2022, 42, 1280–1342. [Google Scholar] [CrossRef]
- Vakser, I.A. Protein-protein docking: From interaction to interactome. Biophys. J. 2014, 107, 1785–1793. [Google Scholar] [CrossRef]
- Pereira, G.P.; Jiménez-García, B.; Pellarin, R.; Launay, G.; Wu, S.; Martin, J.; Souza, P.C.T. Rational Prediction of PROTAC-Compatible Protein-Protein Interfaces by Molecular Docking. J. Chem. Inf. Model. 2023, 63, 6823–6833. [Google Scholar] [CrossRef] [PubMed]
- Zhang, L.; Buck, M. Molecular simulations of a dynamic protein complex: Role of salt-bridges and polar interactions in configurational transitions. Biophys. J. 2013, 10, 2412–2417. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Hu, B.; Lill, M.A. Exploring the potential of protein-based pharmacophore models in ligand pose prediction and ranking. J. Chem. Inf. Model. 2013, 53, 1179–1190. [Google Scholar] [CrossRef][Green Version]
- Guo, Z.; Yamaguchi, R. Machine learning methods for protein-protein binding affinity prediction in protein design. Front. Bioinform. 2022, 2, 1065703. [Google Scholar] [CrossRef]
- Drummond, M.L.; Williams, C.I. In Silico Modeling of PROTAC-Mediated Ternary Complexes: Validation and Application. J. Chem. Inf. Model. 2019, 59, 1634–1644. [Google Scholar] [CrossRef]
- Zaidman, D.; Prilusky, J.; London, N. PRosettaC: Rosetta Based Modeling of PROTAC Mediated Ternary Complexes. J. Chem. Inf. Model. 2020, 60, 4894–4903. [Google Scholar] [CrossRef]
- Bai, N.; Miller, S.A.; Andrianov, G.V.; Yates, M.; Kirubakaran, P.; Karanicolas, J. Rationalizing PROTAC-Mediated Ternary Complex Formation Using Rosetta. J. Chem. Inf. Model. 2021, 61, 1368–1382. [Google Scholar] [CrossRef]
- Bai, N.; Riching, K.M.; Makaju, A.; Wu, H.; Acker, T.M.; Ou, S.C.; Zhang, Y.; Shen, X.; Bulloch, D.N.; Rui, H.; et al. Modeling the CRL4A ligase complex to predict target protein ubiquitination induced by cereblon-recruiting PROTACs. J. Biol. Chem. 2020, 298, 101653. [Google Scholar] [CrossRef]
- Weng, G.; Li, D.; Kang, Y.; Hou, T. Integrative Modeling of PROTAC-Mediated Ternary Complexes. J. Med. Chem. 2021, 64, 16271–16281. [Google Scholar] [CrossRef]
- Tu, Y.; Sun, Y.; Qiao, S.; Luo, Y.; Liu, P.; Jiang, Z.X.; Hu, Y.; Wang, Z.; Huang, P.; Wen, S. Design, Synthesis, and Evaluation of VHL-Based EZH2 Degraders to Enhance Therapeutic Activity against Lymphoma. J. Med. Chem. 2021, 64, 10167–10184. [Google Scholar] [CrossRef] [PubMed]
- Liao, J.; Nie, X.; Unarta, I.C.; Ericksen, S.S.; Tang, W. In Silico Modeling and Scoring of PROTAC-Mediated Ternary Complex Poses. J. Med. Chem. 2022, 65, 6116–6132. [Google Scholar] [CrossRef]
- Weerakoon, D.; Carbajo, R.J.; De Maria, L.; Tyrchan, C.; Zhao, H. Impact of PROTAC Linker Plasticity on the Solution Conformations and Dissociation of the Ternary Complex. J. Chem. Inf. Model. 2022, 62, 340–349. [Google Scholar] [CrossRef] [PubMed]
- Li, W.; Zhang, J.; Guo, L.; Wang, Q. Importance of Three-Body Problems and Protein-Protein Interactions in Proteolysis-Targeting Chimera Modeling: Insights from Molecular Dynamics Simulations. J. Chem. Inf. Model. 2022, 62, 523–532. [Google Scholar] [CrossRef] [PubMed]
- Mai, H.; Zimmer, M.H.; Miller, T.F. Exploring PROTAC Cooperativity with Coarse-Grained Alchemical Methods. J. Phys. Chem. 2023, 127, 446–455. [Google Scholar] [CrossRef]
- Yokoo, H.; Shibata, N.; Endo, A.; Ito, T.; Yanase, Y. Discovery of a Highly Potent and Selective Degrader Targeting Hematopoietic Prostaglandin D Synthase via In Silico Design. J. Med. Chem. 2021, 64, 15868–15882. [Google Scholar] [CrossRef]
- Rao, A.; Tunjic, T.M.; Brunsteiner, M.; Michael, M.; Hosein, F.; Noah, W. Bayesian Optimization for Ternary Complex Prediction (BOTCP). Artif. Intell. Life Sci. 2022, 3, 100072. [Google Scholar] [CrossRef]
- Zheng, S.; Tan, Y.; Wang, Z.; Li, C.; Zhang, Z.; Sang, X.; Chen, H.; Yang, Y. Accelerated rational PROTAC design via deep learning and molecular simulations. Nat. Mach. Intell. 2022, 4, 739–748. [Google Scholar] [CrossRef]
- Li, F.; Hu, Q.; Zhang, X.; Sun, R.; Liu, Z.; Wu, S.; Tian, S.; Ma, X.; Dai, Z.; Yang, X.; et al. DeepPROTACs is a deep learning-based targeted degradation predictor for PROTACs. Nat. Commun. 2022, 13, 7133. [Google Scholar] [CrossRef]
- Nori, D.; Coley, C.W.; Mercado, R. De novo PROTAC design using graph-based deep generative models. arXiv 2022, arXiv:2211.02660, 202. [Google Scholar]
- Zhang, W.; Roy Burman, S.S.; Chen, J.; Donovan, K.A.; Cao, Y.; Shu, C.; Zhang, B.; Zeng, Z.; Gu, S.; Zhang, Y.; et al. Machine Learning Modeling of Protein-intrinsic Features Predicts Tractability of Targeted Protein Degradation. Genom. Proteom. Bioinform. 2022, 20, 882–898. [Google Scholar] [CrossRef] [PubMed]
- Poongavanam, V.; Kölling, F.; Giese, A.; Göller, A.H.; Lehmann, L.; Meibom, D.; Kihlberg, J. Predictive Modeling of PROTAC Cell Permeability with Machine Learning. ACS Omega 2023, 8, 5901–5916. [Google Scholar] [CrossRef]
- Rovers, E.; Schapira, M. Benchmarking of PROTAC docking and virtual screening tools. bioRxiv 2023. [Google Scholar] [CrossRef]
Features | Description |
---|---|
Length |
|
Flexibility |
|
Chemical Composition |
|
Cleavability |
|
Cell Permeability |
|
Hydrophilicity/ Hydrophobicity |
|
Specificity |
|
In vivo Stability |
|
Structural Diversity |
|
Model | Method | Description | Ref |
---|---|---|---|
DeLinker | Graph-based deep generative. |
| [60] |
Link–INVENT | Recurrent Neural Network (RNN) and Reinforcement Learning. |
| [61] |
AIMLinker | Graph Neural Network (GNN). |
| [62] |
DRlinker | Deep Reinforcement Learning. |
| [63] |
ShapeLinker | Reinforcement Learning. |
| [64] |
PROTAC–INVENT | Reinforcement Learning. |
| [65] |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Danishuddin; Jamal, M.S.; Song, K.-S.; Lee, K.-W.; Kim, J.-J.; Park, Y.-M. Revolutionizing Drug Targeting Strategies: Integrating Artificial Intelligence and Structure-Based Methods in PROTAC Development. Pharmaceuticals 2023, 16, 1649. https://doi.org/10.3390/ph16121649
Danishuddin, Jamal MS, Song K-S, Lee K-W, Kim J-J, Park Y-M. Revolutionizing Drug Targeting Strategies: Integrating Artificial Intelligence and Structure-Based Methods in PROTAC Development. Pharmaceuticals. 2023; 16(12):1649. https://doi.org/10.3390/ph16121649
Chicago/Turabian StyleDanishuddin, Mohammad Sarwar Jamal, Kyoung-Seob Song, Keun-Woo Lee, Jong-Joo Kim, and Yeong-Min Park. 2023. "Revolutionizing Drug Targeting Strategies: Integrating Artificial Intelligence and Structure-Based Methods in PROTAC Development" Pharmaceuticals 16, no. 12: 1649. https://doi.org/10.3390/ph16121649
APA StyleDanishuddin, Jamal, M. S., Song, K.-S., Lee, K.-W., Kim, J.-J., & Park, Y.-M. (2023). Revolutionizing Drug Targeting Strategies: Integrating Artificial Intelligence and Structure-Based Methods in PROTAC Development. Pharmaceuticals, 16(12), 1649. https://doi.org/10.3390/ph16121649