دورية أكاديمية
Exploring PROTAC Cooperativity with Coarse-Grained Alchemical Methods.
| العنوان: | Exploring PROTAC Cooperativity with Coarse-Grained Alchemical Methods. |
|---|---|
| المؤلفون: | Mai H; Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California91125, United States., Zimmer MH; Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California91125, United States., Miller TF 3rd; Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California91125, United States. |
| المصدر: | The journal of physical chemistry. B [J Phys Chem B] 2023 Jan 19; Vol. 127 (2), pp. 446-455. Date of Electronic Publication: 2023 Jan 06. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S. |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 101157530 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-5207 (Electronic) Linking ISSN: 15205207 NLM ISO Abbreviation: J Phys Chem B Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, D.C. : American Chemical Society, c1997- |
| مواضيع طبية MeSH: | Ubiquitin-Protein Ligases*/chemistry , Ubiquitin-Protein Ligases*/metabolism , Proteins*/metabolism, Proteolysis ; Thermodynamics |
| مستخلص: | Proteolysis targeting chimera (PROTAC) is a novel drug modality that facilitates the degradation of a target protein by inducing proximity with an E3 ligase. In this work, we present a new computational framework to model the cooperativity between PROTAC-E3 binding and PROTAC-target binding principally through protein-protein interactions (PPIs) induced by the PROTAC. Due to the scarcity and low resolution of experimental measurements, the physical and chemical drivers of these non-native PPIs remain to be elucidated. We develop a coarse-grained (CG) approach to model interactions in the target-PROTAC-E3 complexes, which enables converged thermodynamic estimations using alchemical free energy calculation methods despite an unconventional scale of perturbations. With minimal parametrization, we successfully capture fundamental principles of cooperativity, including the optimality of intermediate PROTAC linker lengths that originates from configurational entropy. We qualitatively characterize the dependency of cooperativity on PROTAC linker lengths and protein charges and shapes. Minimal inclusion of sequence- and conformation-specific features in our current force field, however, limits quantitative modeling to reproduce experimental measurements, but further development of the CG model may allow for efficient computational screening to optimize PROTAC cooperativity. |
| References: | Cell. 2020 Dec 10;183(6):1714-1731.e10. (PMID: 33275901) PLoS One. 2008 Jan 23;3(1):e1487. (PMID: 18213395) J Med Chem. 2021 Jun 24;64(12):8042-8052. (PMID: 34106704) ACS Chem Biol. 2019 Nov 15;14(11):2430-2440. (PMID: 31059647) J Chem Inf Model. 2022 Jun 27;62(12):3023-3033. (PMID: 35679463) Curr Opin Chem Biol. 2019 Oct;52:145-156. (PMID: 31419624) Nat Chem Biol. 2019 Jul;15(7):672-680. (PMID: 31178587) J Chem Phys. 2008 Sep 28;129(12):124105. (PMID: 19045004) J Mol Biol. 2017 Apr 7;429(7):930-947. (PMID: 27908641) Cell Chem Biol. 2018 Jan 18;25(1):78-87.e5. (PMID: 29129718) Nat Chem Biol. 2019 Jul;15(7):737-746. (PMID: 31209349) Proc Natl Acad Sci U S A. 2018 Jul 31;115(31):E7285-E7292. (PMID: 30012605) J Med Chem. 2022 Apr 28;65(8):6116-6132. (PMID: 35412837) Phys Rev Lett. 2008 Dec 12;101(24):248301. (PMID: 19113678) PLoS Comput Biol. 2017 Mar 22;13(3):e1005427. (PMID: 28328943) J Comput Aided Mol Des. 2015 May;29(5):397-411. (PMID: 25808134) Medchemcomm. 2019 Aug 12;10(10):1755-1764. (PMID: 31867093) Nat Chem Biol. 2021 Feb;17(2):152-160. (PMID: 33199914) Living J Comput Mol Sci. 2020;2(1):. (PMID: 34458687) Explor Target Antitumor Ther. 2020;1(5):273-312. (PMID: 36046485) Nat Rev Drug Discov. 2021 Apr;20(4):247-250. (PMID: 33737725) Drug Discov Today. 2020 Sep;25(9):1585-1591. (PMID: 32565163) J Mol Biol. 2019 Mar 29;431(7):1481-1493. (PMID: 30776430) Nat Commun. 2017 Oct 10;8(1):830. (PMID: 29018234) Protein Sci. 2021 Feb;30(2):438-447. (PMID: 33244804) J Chem Inf Model. 2022 Feb 14;62(3):523-532. (PMID: 35084845) Cell Chem Biol. 2021 Jul 15;28(7):1048-1060. (PMID: 33811812) Nat Commun. 2019 Jan 10;10(1):131. (PMID: 30631068) J Comput Chem. 2010 Jan 30;31(2):317-42. (PMID: 19462412) J Med Chem. 2018 Jan 25;61(2):504-513. (PMID: 28595007) J Med Chem. 2022 Jun 23;65(12):8113-8126. (PMID: 35658428) Angew Chem Int Ed Engl. 2016 Jan 11;55(2):807-10. (PMID: 26593377) Curr Opin Struct Biol. 2017 Jun;44:31-38. (PMID: 27866112) EBioMedicine. 2018 Oct;36:553-562. (PMID: 30224312) J Chem Inf Model. 2020 Oct 26;60(10):4894-4903. (PMID: 32976709) Nat Chem Biol. 2019 Jul;15(7):747-755. (PMID: 31209351) Nat Chem Biol. 2018 Jul;14(7):706-714. (PMID: 29892083) Cell Chem Biol. 2021 Jul 15;28(7):1000-1013. (PMID: 33891901) ACS Chem Biol. 2019 Mar 15;14(3):361-368. (PMID: 30721025) Phys Chem Chem Phys. 2010 Mar 28;12(12):2850-9. (PMID: 20449375) ACS Med Chem Lett. 2022 Jun 20;13(7):1182-1190. (PMID: 35859867) Cell Chem Biol. 2018 Jan 18;25(1):88-99.e6. (PMID: 29129717) ACS Cent Sci. 2021 Jul 28;7(7):1117-1125. (PMID: 34345664) J Phys Chem B. 2022 Oct 6;126(39):7510-7527. (PMID: 35787023) J Chem Inf Model. 2020 Oct 26;60(10):5234-5254. (PMID: 32969649) Nat Biotechnol. 2021 May;39(5):630-641. (PMID: 33398154) J Chem Theory Comput. 2021 Apr 13;17(4):2457-2464. (PMID: 33709712) Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8554-9. (PMID: 11438690) J Med Chem. 2021 Nov 11;64(21):16271-16281. (PMID: 34709816) J Phys Chem B. 2010 Aug 19;114(32):10235-53. (PMID: 20701361) J Biol Chem. 2021 Jan-Jun;296:100647. (PMID: 33839157) ACS Chem Biol. 2021 Nov 19;16(11):2228-2243. (PMID: 34582690) J Chem Inf Model. 2021 Mar 22;61(3):1368-1382. (PMID: 33625214) Nat Chem Biol. 2017 May;13(5):514-521. (PMID: 28288108) Cell. 2020 Apr 2;181(1):102-114. (PMID: 31955850) Cell Rep. 2012 Oct 25;2(4):927-37. (PMID: 23084746) J Biol Chem. 2022 Apr;298(4):101653. (PMID: 35101445) Angew Chem Int Ed Engl. 2020 Jan 20;59(4):1727-1734. (PMID: 31746102) ACS Chem Biol. 2018 Sep 21;13(9):2758-2770. (PMID: 30137962) Structure. 2019 Nov 5;27(11):1625-1633.e3. (PMID: 31693911) |
| معلومات مُعتمدة: | R01 GM138845 United States GM NIGMS NIH HHS |
| المشرفين على المادة: | EC 2.3.2.27 (Ubiquitin-Protein Ligases) 0 (Proteins) |
| تواريخ الأحداث: | Date Created: 20230106 Date Completed: 20230120 Latest Revision: 20230926 |
| رمز التحديث: | 20230926 |
| مُعرف محوري في PubMed: | PMC9869335 |
| DOI: | 10.1021/acs.jpcb.2c05795 |
| PMID: | 36607139 |
| قاعدة البيانات: | MEDLINE |
Find this issue from the American Chemical Society | تدمد: | 1520-5207 |
|---|---|
| DOI: | 10.1021/acs.jpcb.2c05795 |