Competitive Inhibition of Cortisol by Prostaglandins at the Ligand Binding Domain of Glucocorticoid Receptors

Schaper, Charles

doi:10.1101/851501

Cited by 11 publications

(27 citation statements)

References 22 publications

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“…• Molecule Selection: The A-T pairing was selected for the simulations to evaluate the positioning of the third hydrogen bond relative to the corticosteroid molecule. Cortisol was selected for the study because of a prior study that I conducted on its interaction with prostaglandins in producing fevers and symptoms of other diseases [14], of which a molecular basis for this interaction was sought, indicating competitive inhibition of cortisol by prostaglandings [13]. This investigation led to the development of the calcium ions as a differentiated factor between the expression of steroids and non-expression of non-steroidal molecules capable of occupying the ligand binding domain of cortisol.…”

Section: Methodsmentioning

confidence: 99%

“…Some resetting of the initial conditions to different arrangements were made in order to arrive at a reasonable configuration of nucleotides. The cortisol molecule, and later the PGE2 molecule, were coordinated with the ligand binding domain amino acids of the glucocorticoid receptor, as well as two calcium ions, using previously described methods [13]. The cortisol molecule and the positioning of the calcium ions were then extracted from the LBD and placed in close proximity to the DNA molecule.…”

Section: Methodsmentioning

confidence: 99%

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Endogenous Binding of Steroid Molecules to DNA Nucleotides by a Ca2+/PO4- Process to Enable Gene Transcription

Schaper¹

2020

Preprint

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Steroid hormones, such as cortisol, testosterone and estrogen, have powerful control over human physiology, growth, and reproduction, but efforts to deploy its potential, such as with glucocorticoids, a first-line defense of inflammation, are often met with severe side effects. Unfortunately, much is unknown about the basic interaction of steroid molecules with DNA, including its receptors, activators, factors, and the gene transcription procedure. In this research article, a remarkable finding is shown for the first time, in which it is illustrated through structural analysis that the base pairings of the four DNA nucleotides, adenine with thymine (A-T) and cytosine with guanine (C-G), form perfectly the classic four ring structure of the steroid molecule, which indicates the profound result put forth in this article that steroid molecules bind directly to DNA for the purpose of gene transcription. Further, critical to a basic understanding of DNA, it is resolved here of the location of the unusual ``missing" hydrogen bond of the A-T pairing, which has only two internal hydrogen bonds whereas C-G has three hydrogen bonds. It is shown that the third hydrogen bond for A-T is formed when the A-T nucleotide is coupled with corticosteroids, such as cortisol, which has an oxygen functional group that is perfectly positioned to form a hydrogen bond with the accessible oxygen-based functional group of thymine. In addition, to facilitate the binding process, it is shown that Ca2+ ions, which are associated with the ligand binding domain of the steroid receptor prior to its association with DNA, couple the oxygen-based functional groups at each end of the steroid molecule with the PO4- ions of adjacent nucleotides and thus bind the steroid molecule directly to the nucleic acid. The results are further amplified by analysis of the cortisol hormone and the ligand binding domain of the glucocorticoid receptor in its interaction with the A-T nucleotide pairing.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Endogenous Binding of Steroid Molecules to DNA Nucleotides by a Ca2+/PO4- Process to Enable Gene Transcription

Schaper¹

2020

Preprint

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“…The optimization routine was utilized to determine the lowest energy state. Using previously described methods [22], the calcium and magnesium ions were coupled to the DNA nucleotides with the steroid hormone.…”

Section: Methodsmentioning

confidence: 99%

Structural Symmetry of DNA Nucleotides and Steroid Hormones

Schaper

2020

Preprint

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DNA is comprised of important structural characteristics, which include the complementary base pairs of adenine-thymine (A-T) and cytosine-guanine (C-G) that serve to initiate and code for transcription and translation into amino acids. Recently, structural analysis of DNA performed in this lab indicated that each DNA nucleotide complementary base pair is in perfect correspondence with the structure of the steroid molecule and steroid hormones. Here, detailed structural analysis and illustrations are presented to clearly support and extend this fundamental finding. The structural illustrations indicate that the DNA Nucleotide base pairs can achieve perfect alignment with steroid hormones, such that each of its functional groups can be assigned a purpose for binding, stabilization, and transcription regulation. The relation of the missing third hydrogen bond for A-T and T-A, relative to the three hydrogen bonds of C-G and G-C, is clearly shown to be found through its coupling with the class of corticosteroids like cortisol that have an oxygen group perfectly positioned for interaction with the available functional group of thymine. Thus the intermolecular coupling by hydrogen bonding of Cortisol-Thymine produces a strong complex. Moreover, the structural analysis of the end group couplings to an ionic linkage element, Ca2+ or Mg2+, demonstrate interaction with both the DNA phosphates as well as the oxygen element within the sugar. The relationships confirm a structural association of cortisol-like steroid hormones with A-T and T-A and a structural association of testosterone-like steroid hormones for G-C and C-G. Synthetic steroids are assessed, including prednisolone and dexamethasone, to indicate consistency of the functional group interactions with the DNA base pairs, phosphate, and sugar groups to support and confirm direct binding and structural correspondence of steroid hormones to DNA Nucleotides.

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“…Molecular modeling indicated that the GR-PGE2 structure was actually at a lower energy state than that of GR-PGE2. The results were documented in the preprint [5].…”

Section: Introductionmentioning

confidence: 99%

“…Through molecular models, it has been shown in [5] that PGE2 can be conformed such that it and cortisol (CORT) will have a similar arrangement of chemical elements 130 and functional groups which would permit equivalent affinity with the LBD of GR. Cells containing GR are found in almost every cell and tissue, but should be particularly relevant to the hypothalamus that is the control site for temperature, and the site for control of the HPA axis in response to cortisol.…”

Section: Introductionmentioning

confidence: 99%

Molecular Pathways Resultant in Fever due to Inhibitory Effects of Binding PGE2 to Glucocorticoid Receptors

Schaper

2020

Preprint

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5Thermoregulation is crucial to homeostasis, but the mechanisms of its dysfunction are still largely mysterious, including fever, which is generally the most disconcerting sign of a serious infection or disease. Theories on body temperature dynamics that aim to explain a fever, such as changes in an internal setpoint, have been proposed, but none can identify the fundamental molecular pathways that produce a fever. Moreover, 10 causative substances, pyrogens such as prostaglandin E2 (PGE2), have not been associated with receptors at the hypothalamus, which is responsible for autonomic control of temperature, and therefore no molecular path has been previously identified that can elucidate the causative reason for fever. Here, molecular pathways resultant in fever are identified for the first time. Based on recent developments made by this lab, 15 which has shown that PGE2 possesses similar binding affinity as the hormone cortisol (CORT) at the critical ligand binding domain (LBD) of glucocorticoid receptors (GR); mathematical modeling and a case study for validation is used to present that competitive inhibition of CORT by PGE2 as the fundamental reason for dysfunctional dynamics of body temperature, including fever. The model characterizing temperature 20 is in the form of a multivariable feedback controller comprised of a superposition of proportional and derivative terms of temperature, CORT, and PGE2 concentration at the hypothalamus thereby linking the cardiovascular, immune, and neural systems. The model constitutes a framework of linear equations that describes a closed-loop system of body temperature effects in response to infectious agents, triggering events, 25 * cschaper@transferdevices.com Graphical Abstract 65Here, the newly found association of CORT and PGE2 at the LBD is used to revisit the mathematical model of fever previously derived absent chemistry, although the model predicted its characteristics. Here, material and energy relations are added for CORT and PGE2, including the hypothalamic-pituitary-adrenal (HPA) axis, and the pathways are specified and integrated into the model to analyze temperature and fever. The model 85 is verified by comparing it to the case history of the temperature response including hypothermia and hyperthermia. Thus, a basic framework is developed for thermoregulation, which is vital to homeostasis and to understanding of basic physiology.Moreover, this study on fevers can be adapted to other signs and symptoms of disease, particularly infections. As the hypothalamus is the central controller of the autonomic 90 nervous system, disruption due to the processing of cortisol via prostaglandins, will cause misprocessing of other functions besides temperature. In a similar manner, other aspects such as fatigue and even emotional dysfunction, such as depression, may be impacted by disease through the molecular pathways described in this article. Some of these issues are described in the discussion section. 2 ResultsIt is the thesis of this article that through the competit...

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Competitive Inhibition of Cortisol by Prostaglandins at the Ligand Binding Domain of Glucocorticoid Receptors

Cited by 11 publications

References 22 publications

Endogenous Binding of Steroid Molecules to DNA Nucleotides by a Ca2+/PO4- Process to Enable Gene Transcription

Endogenous Binding of Steroid Molecules to DNA Nucleotides by a Ca2+/PO4- Process to Enable Gene Transcription

Structural Symmetry of DNA Nucleotides and Steroid Hormones

Molecular Pathways Resultant in Fever due to Inhibitory Effects of Binding PGE2 to Glucocorticoid Receptors

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