دورية أكاديمية
أعرض في EDS

Unveiling therapeutic frontiers: DON/DRP-104 as innovative Plasma kallikrein inhibitors against carcinoma-associated hereditary angioedema shocks - a comprehensive molecular dynamics exploration.

التفاصيل البيبلوغرافية
العنوان: Unveiling therapeutic frontiers: DON/DRP-104 as innovative Plasma kallikrein inhibitors against carcinoma-associated hereditary angioedema shocks - a comprehensive molecular dynamics exploration.
المؤلفون: Oduro-Kwateng E; Molecular Bio-Computation and Drug Design Research Group, School of Health Sciences, University of KwaZulu Natal, Westville Campus, Durban, 4001, South Africa., Soliman MES; Molecular Bio-Computation and Drug Design Research Group, School of Health Sciences, University of KwaZulu Natal, Westville Campus, Durban, 4001, South Africa. soliman@ukzn.ac.za.
المصدر: Cell biochemistry and biophysics [Cell Biochem Biophys] 2024 Jun; Vol. 82 (2), pp. 1159-1177. Date of Electronic Publication: 2024 Jun 13.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Humana Press Country of Publication: United States NLM ID: 9701934 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1559-0283 (Electronic) Linking ISSN: 10859195 NLM ISO Abbreviation: Cell Biochem Biophys Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Totowa, NJ : Humana Press, c1996-
مواضيع طبية MeSH: Molecular Dynamics Simulation* , Angioedemas, Hereditary*/drug therapy , Plasma Kallikrein*/antagonists & inhibitors , Plasma Kallikrein*/metabolism, Humans ; Hydrogen Bonding ; Neoplasms/drug therapy ; Prodrugs/chemistry ; Prodrugs/pharmacology ; Prodrugs/therapeutic use ; Molecular Docking Simulation
مستخلص: Human plasma kallikrein (PKa) is a member of the serine protease family and serves as a key mediator of the kallikrein-kinin system (KKS), which is known for its regulatory roles in inflammation, vasodilation, blood pressure, and coagulation. Genetic dysregulation of KKS leads to Hereditary Angioedema (HAE), which is characterized by spontaneous, painful swelling in various body regions. Importantly, HAE frequently coexists with various cancers. Despite substantial efforts towards the development of PKa inhibitors for HAE, there remains a need for bifunctional agents addressing both anti-cancer and anti-HAE aspects, especially against carcinoma-associated comorbid HAE conditions. Consequently, we investigated the therapeutic potential of the anti-glutamine prodrug, isopropyl(S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)-propanamido)-6-diazo-5-oxo-hexanoate (DRP-104), and its active form, 6-Diazo-5-oxo-l-norleucine (DON), recognized for their anti-cancer properties, as novel PKa inhibitors. Utilizing structure-based in silico methods, we conducted a comparative analysis with berotralstat, a clinically approved HAE prophylactic, and sebetralstat, an investigational HAE therapeutic agent, in Phase 3 clinical trials. Inhibiting PKa with DON resulted in relatively heightened structural stability, rigidity, restricted protein folding, and solvent-accessible loop exposure, contributing to increased intra-atomic hydrogen bond formation. Conversely, PKa inhibition with DRP-104 induced restricted residue flexibility and significantly disrupted the critical SER195-HIS57 arrangement in the catalytic triad. Both DON and DRP-104, along with the reference drugs, induced strong cooperative intra-residue motion and bidirectional displacement in the PKa architecture. The results revealed favorable binding kinetics of DON/DRP-104, showing thermodynamic profiles that were either superior or comparable to those of the reference drugs. These findings support their consideration for clinical investigations into the management of carcinoma-associated HAE.
(© 2024. The Author(s).)
References: J Pharmacol Exp Ther. 2023 Nov;387(2):214-225. (PMID: 37643795)
J Chem Inf Model. 2021 Apr 26;61(4):1954-1969. (PMID: 33739090)
Proc Natl Acad Sci U S A. 2012 Oct 30;109(44):17845-50. (PMID: 22822217)
J Med Chem. 2022 Oct 27;65(20):13629-13644. (PMID: 36251573)
J Comput Chem. 2010 Jan 30;31(2):455-61. (PMID: 19499576)
Eur J Med Chem. 2020 Mar 15;190:112137. (PMID: 32066009)
J Mol Graph Model. 2006 Oct;25(2):247-60. (PMID: 16458552)
Anticancer Res. 2018 Dec;38(12):6801-6807. (PMID: 30504393)
Comput Struct Biotechnol J. 2019 Jul 26;17:1162-1170. (PMID: 31462972)
J Med Chem. 2021 Sep 9;64(17):12453-12468. (PMID: 34436898)
J Allergy Clin Immunol Pract. 2022 Mar;10(3):716-722. (PMID: 34838707)
BMC Cancer. 2018 Apr 4;18(1):382. (PMID: 29618333)
Biol Chem. 2008 Sep;389(9):1225-33. (PMID: 18713009)
ACS Med Chem Lett. 2016 Dec 06;8(2):185-190. (PMID: 28197309)
Cancer Genet Cytogenet. 1997 Jun;95(2):159-62. (PMID: 9169034)
Adv Appl Bioinform Chem. 2015 Nov 19;8:37-47. (PMID: 26604800)
Nihon Kokyuki Gakkai Zasshi. 2004 May;42(5):435-9. (PMID: 15168463)
J Comput Chem. 2004 Oct;25(13):1605-12. (PMID: 15264254)
JMIR Bioinform Biotechnol. 2020 Jun 19;1(1):e14232. (PMID: 38943236)
J Struct Biol. 2019 May 1;206(2):170-182. (PMID: 30876891)
Sci Adv. 2022 Nov 18;8(46):eabq5925. (PMID: 36383674)
Allergy Asthma Clin Immunol. 2021 Dec 19;17(1):134. (PMID: 34924008)
RSC Adv. 2020 Jun 19;10(39):23466-23483. (PMID: 35520325)
Protein Sci. 2008 Dec;17(12):2023-37. (PMID: 18824507)
J Biol Chem. 2005 Dec 9;280(49):41077-89. (PMID: 16199530)
Mol Cancer Ther. 2022 Oct 7;21(10):1561-1572. (PMID: 35930753)
Expert Opin Drug Discov. 2015 May;10(5):449-61. (PMID: 25835573)
J Chem Theory Comput. 2013 Jul 9;9(7):3084-95. (PMID: 26583988)
N Engl J Med. 2010 Aug 5;363(6):523-31. (PMID: 20818887)
Front Physiol. 2023 Aug 30;14:1188816. (PMID: 37711466)
Medicina (Kaunas). 2023 Mar 24;59(4):. (PMID: 37109602)
Immunotherapy. 2019 Aug;11(11):937-944. (PMID: 31234673)
J Thromb Haemost. 2019 May;17(5):759-770. (PMID: 30801944)
J Chem Phys. 2019 May 28;150(20):204110. (PMID: 31153204)
Biomolecules. 2022 Sep 17;12(9):. (PMID: 36139154)
J Cheminform. 2012 Aug 13;4(1):17. (PMID: 22889332)
J Mol Model. 2009 Sep;15(9):1093-108. (PMID: 19234730)
J Chem Inf Model. 2011 Oct 24;51(10):2778-86. (PMID: 21919503)
J Cell Biochem. 2024 Jan 29;:. (PMID: 38284235)
Chem Biodivers. 2022 Feb;19(2):e202100646. (PMID: 34982514)
Acc Chem Res. 2000 Dec;33(12):889-97. (PMID: 11123888)
ACS Med Chem Lett. 2022 Jul 29;13(8):1217-1218. (PMID: 35978687)
فهرسة مساهمة: Keywords: Cancer; DRP-104; Hereditary Angioedema; Plasma kallikrein; molecular dynamics
المشرفين على المادة: EC 3.4.21.34 (Plasma Kallikrein)
0 (Prodrugs)
تواريخ الأحداث: Date Created: 20240613 Date Completed: 20240824 Latest Revision: 20240827
رمز التحديث: 20240827
مُعرف محوري في PubMed: PMC11344713
DOI: 10.1007/s12013-024-01266-0
PMID: 38869687
قاعدة البيانات: MEDLINE
الوصف
تدمد:1559-0283
DOI:10.1007/s12013-024-01266-0