The modulatory role of sulfated and non-sulfated small molecule heparan sulfate-glycomimetics in endothelial dysfunction: absolute structural clarification, molecular docking and simulated dynamics, SAR analyses and ADMET studies

Gill, Deborah; Povinelli, Ana Paula Ribeiro; Zazeri, Gabriel; S, Shamir; Mahmoud, Ayman M.; Wilkinson, Fiona L.; Alexander, M; Cornélio, Marinônio Lopes; Jones, Alan M.

doi:10.1039/d0md00366b

Cited by 16 publications

(13 citation statements)

References 25 publications

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“…The recently developed sulfation by tributylsulfoammonium betaine (TBSAB; SO 3 ·NBu 3 ) [ 19 ] has proven effective on a variety of phenolic substrates, including steroids [ 34 ] and phenolic acid salts and esters [ 35 ]. A modification of this method uses a SO 3 -pyridine complex, followed by the addition of tributylamine [ 36 ].…”

Section: Resultsmentioning

confidence: 99%

Sulfation of Phenolic Acids: Chemoenzymatic vs. Chemical Synthesis

Kolaříková

Brodsky

Petrásková

et al. 2022

IJMS

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Phenolic acids are known flavonoid metabolites, which typically undergo bioconjugation during phase II of biotransformation, forming sulfates, along with other conjugates. Sulfated derivatives of phenolic acids can be synthesized by two approaches: chemoenzymatically by 3′-phosphoadenosine-5′-phosphosulfate (PAPS)-dependent sulfotransferases or PAPS-independent aryl sulfotransferases such as those from Desulfitobacterium hafniense, or chemically using SO3 complexes. Both approaches were tested with six selected phenolic acids (2-hydroxyphenylacetic acid (2-HPA), 3-hydroxyphenylacetic acid (3-HPA), 4-hydroxyphenylacetic acid (4-HPA), 3,4-dihydroxyphenylacetic acid (DHPA), 3-(4-hydroxyphenyl)propionic acid (4-HPP), and 3,4-dihydroxyphenylpropionic acid (DHPP)) to create a library of sulfated metabolites of phenolic acids. The sulfates of 3-HPA, 4-HPA, 4-HPP, DHPA, and DHPP were all obtained by the methods of chemical synthesis. In contrast, the enzymatic sulfation of monohydroxyphenolic acids failed probably due to enzyme inhibition, whereas the same reaction was successful for dihydroxyphenolic acids (DHPA and DHPP). Special attention was also paid to the counterions of the sulfates, a topic often poorly reported in synthetic works. The products obtained will serve as authentic analytical standards in metabolic studies and to determine their biological activity.

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Section: Resultsmentioning

confidence: 99%

Sulfation of Phenolic Acids: Chemoenzymatic vs. Chemical Synthesis

Kolaříková

Brodsky

Petrásková

et al. 2022

IJMS

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“…Case-control functional imaging and spectroscopic studies should be correlated with temporal changes in inflammatory biomarker levels. We propose herein that the elevation in HGF identified by Gundry may be related to memory of the chirality found in human heparan sulfate proteoglycans whose composite molecular chirality and L-AA levels are proposed to play important roles in the SSP during chemical evolution [186,187].…”

Section: Urgent Need For Additional Case-control Studies Of Temporal ...mentioning

confidence: 90%

“…Heparin and heparan sulfate structures are examples of molecules whose ensemble, i.e. composite, molecular chirality is very high [224,225,186,187]. Under the ensemble HCC hypothesis, heparin is likely to be one of many biomolecules whose composite chirality is "remembered" by L-AA and the L-AA free radical, which are postulated (herein) to have been involved in their biosynthesis, early in chemical evolution of Life.…”

Section: Protecting the Ecm And Restoring The Egl: Postulated Anaboli...mentioning

confidence: 99%

Are the mRNA vaccines inducing the Sanarelli-Shwartzman phenomenon?

Davidson¹,

Winey²

2022

GSC Adv. Res. Rev.

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Adverse events of myocarditis, pericarditis, and thrombosis, temporally associated with mRNA vaccination(s) and/or mRNA vaccine boosters, have been reported during post-marketing safety surveillance in the U.S. CDC VAERS database and 2021 CDC guidance to physicians. An interim report unexpectedly revealed inflammatory biomarker elevations in vaccine recipients. During review of considerable published research on the Sanarelli-Shwartzman phenomenon (SSP) and the use of nucleic acids as vaccine adjuvants, a novel, hypothesis is proposed. Even today, after being studied for over a century, the pathophysiology of the SSP is not fully understood. Motivated by a paper from 1950, titled “General Adaptation Syndrome” by Hans Selye, and recent published research by Korean investigators, a novel, non-conventional hypothesis was generated. Gluten and lectin sensitivity are cited as examples of sensitizing events of the SSP, for which we propose ensemble hydrophobic chiroptical catalysis may have therapeutic benefit. Under the ensemble HCC hypothesis, we propose that inflammatory stress and scurvy promote loss of chirality control, anomeric fidelity, phenotypic stability, and immune function, both humoral and cell-mediated, with the dialyzable transfer factor, L-ascorbic acid, and spin water playing central roles. It is proposed that therapeutic synergy of L-ascorbic acid, bioflavonoids, and corticosteroids in countering the SARS-CoV-2 pathogen arises from memory of chirality which originated during their biosynthesis. It is proposed that ensemble HCC is powered by radiant and or zero-point energy (quantum vacuum fluctuations) which may support a paradigm shift to supramolecular biology. The distinction between supramolecular biology and supramolecular xenobiology is highlighted.

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“…Pharmacokinetics: ADMET studies "Absorption, distribution, metabolism, excretion, and toxicity (ADMET)" refers to the body's response to a drug that is investigated in pharmacokinetics. 65 Thus, it's essential for early research and development of drugs in addition to ADMET testing, which is applied to assess all of a possible drug's aspects. 66,67 The admetSAR online database shows the Admet features of different heterocyclic amide analogues (3)(4)(5)(6) in Table 4.…”

Section: Pharmacokinetics: Drug-likeness Studiesmentioning

confidence: 99%

Computational and Pharmacokinetic Investigation of Some Heterocyclic Amide Derivatives as Cyclooxygenase Inhibitors: An In-Silico Approach

Kabir¹,

Noyon²,

Uzzaman³

2023

Pharmacogn J.

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The two most significant as well as historically important non-steroidal and anti-inflammatory medications (NSAIDs), aspirin and ibuprofen, are frequently used to treat fever, pain, and inflammation. By blocking the activity of cyclooxygenase (COX), it can prevent the production of prostaglandin. In an effort to examine the physiochemical and biological properties of some heterocyclic amide derivatives and quantum mechanical computations have been used to analyze the compounds. To clarify the thermochemical, molecular orbital, and equilibrium geometrical features in the gas phase, density functional theory (DFT) with the B3LYP/6-31G basis set has been used. Binding affinities and modes of heterocyclic amide analogs have been investigated on human cyclooxygenase (COX-1 and COX-2) proteins (6Y3C and 5F19) using molecular docking as well as nonbonding interactions. Results from geometry and thermochemical analysis support the chemical sustainability of all the structures. Most of the compounds exhibited a significant affinity for binding to the receptor protein (5F19) than the standard drugs aspirin and ibuprofen. The improved pharmacokinetic features of certain derivatives with reduced acute oral toxicity were revealed by ADMET prediction. Overall, four heterocyclic amide analogs 3-6 were found to be more efficient in inhibiting COX-2 (5F19) than COX-1 (6Y3C), suggesting that they may be useful as COX-2-related inflammation drug candidates.

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The modulatory role of sulfated and non-sulfated small molecule heparan sulfate-glycomimetics in endothelial dysfunction: absolute structural clarification, molecular docking and simulated dynamics, SAR analyses and ADMET studies

Abstract: The conceptual technology of small molecule glycomimetics, exemplified by compounds C1–4, has shown promising protective effects against lipid-induced endothelial dysfunction.

Cited by 16 publications

References 25 publications

Sulfation of Phenolic Acids: Chemoenzymatic vs. Chemical Synthesis

Sulfation of Phenolic Acids: Chemoenzymatic vs. Chemical Synthesis

Are the mRNA vaccines inducing the Sanarelli-Shwartzman phenomenon?

Computational and Pharmacokinetic Investigation of Some Heterocyclic Amide Derivatives as Cyclooxygenase Inhibitors: An In-Silico Approach

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