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Metals-triggered compound CDPDP exhibits anti-arthritic behavior by downregulating the inflammatory cytokines, and modulating the oxidative storm in mice models with extensive ADMET, docking and simulation studies

Affiliation
Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs ,School of Pharmacy ,Shanghai Jiao Tong University ,Shanghai ,China
Hassan, Syed Shams ul;
Affiliation
Department of Pharmacy ,Sarhad University of Science and Technology ,Peshawar ,Pakistan
Abbas, Syed Qamar;
Affiliation
Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs ,School of Pharmacy ,Shanghai Jiao Tong University ,Shanghai ,China
Muhammad, Ishaq;
Affiliation
Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs ,School of Pharmacy ,Shanghai Jiao Tong University ,Shanghai ,China
Wu, Jia-Jia;
Affiliation
Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs ,School of Pharmacy ,Shanghai Jiao Tong University ,Shanghai ,China
Yan, Shi-Kai;
Affiliation
Department of Pharmacy ,Kohat University of Science and Technology ,Kohat ,Pakistan
Ali, Fawad;
Affiliation
Faculty of Pharmacy ,Hamdard University ,Islamabad ,Pakistan
Majid, Muhammad;
Affiliation
Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs ,School of Pharmacy ,Shanghai Jiao Tong University ,Shanghai ,China
Jin, Hui-Zi;
Affiliation
Department of Pharmacy ,Faculty of Medicine and Pharmacy ,University of Oradea ,Oradea ,Romania
Bungau, Simona

Graphical Abstract

Triggering through abiotic stress, including chemical triggers like heavy metals, is a new technique for drug discovery. In this research, the effect of heavy metal Nickel on actinobacteria Streptomyces sp. SH-1327 to obtain a stress-derived compound was firstly investigated. A new compound cyclo-(D)-Pro-(D)-Phe (CDPDP) was triggered from the actinobacteria strain SH-1327 with the addition of nickel ions 1 mM. The stress compound was further evaluated for its anti-oxidant, analgesic, and anti-inflammatory activity against rheumatoid arthritis through in-vitro and in-vivo assays in albino mice. A remarkable in-vitro anti-oxidant potential of CDPDP was recorded with the IC 50 value of 30.06 ± 5.11 μg/ml in DPPH, IC 50 of 18.98 ± 2.91 against NO free radicals, the IC 50 value of 27.15 ± 3.12 against scavenging ability and IC 50 value of 28.40 ± 3.14 μg/ml for iron chelation capacity. Downregulation of pro-inflammatory mediators (NO and MDA), suppressed levels of pro-inflammatory cytokines (TNF-α, IL-6, IL-Iβ) and upregulation of expressions of anti-oxidant enzymes (GSH, catalase, and GST) unveiled its anti-inflammatory potential. CDPDP was analyzed in human chondrocyte cell line CHON-001 and the results demonstrated that CDPDP significantly increased cell survival, and inhibited apoptosis of IL-1β treated chondrocytes and IL-1β induced matrix degrading markers. In addition, to evaluate the mitochondrial fitness of CHON-001 cells, CDPDP significantly upregulated pgc1-α, the master regulator of mitochondrial biogenesis, indicating that CDPDP provides protective effects in CHON-001 cells. The absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile of the CDPDP showed that CDPDP is safe in cases of hepatotoxicity, cardiotoxicity, and cytochrome inhibition. Furthermore, docking results showed good binding of CDPDP with IL-6–17.4 kcal/mol, and the simulation studies proved the stability between ligand and protein. Therefore, the findings of the current study prospect CDPDP as a potent anti-oxidant and a plausible anti-arthritic agent with a strong pharmacokinetic and pharmacological profile.

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License Holder: Copyright © 2022 Hassan, Abbas, Muhammad, Wu, Yan, Ali, Majid, Jin and Bungau.

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