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GPCRs of diverse physiologic and pathologic effects with their fingerprints in COVID-19

G-protein-coupled receptors (GPCR), a seven-transmembrane α-helical domain protein, contribute to many physiologic functions including vision, olfaction and taste and also to several pathologic processes including hypersensitivity to angiotensin II, inflammatory and vascular diseases [1, 2]. GPCRs in binding with agonistic ligands adopt a proton-transport dependent conformational change and activate cytoplasmic heterotrimeric G proteins (Gα/Gβγ subunits) through dissociation of Gα from Gβγ complex and exchange of GTP for GDP in Gα subunit [3, 4]. This activates a second messenger including cAMP, Ca2+, diacylglycerol which induces some intracellular pathways such as MAPK, PI3K-Akt and Ras and Rho GTPases [5]. Moreover, GPCR activation promotes receptor phosphorylation by GPCR-kinase with subsequent binding of β-arrestin which induces G-protein independent signaling cascades [6, 7].

COVID-19-induced inflammatory cascade has been attributed to ACE2 downregulation and imbalance of proinflammatory ACE/AngII/AT1R and anti-inflammatory ACE2/Angiotensin(1-7)/Mas axes in favor of the former [8]. AT1R, AT2R and Mas receptors belong to GPCR family [9, 10]. While sustained AngII activation of AT1R induces inflammatory responses through G-proteins, angiotensin(1-7) promotes anti-inflammatory effects both via Mas/GPCR receptors and AT1R/GPCR mediated β-arrestin pathway [11]. SARS-CoV2 has been suggested to induce lung edema via activation of GPCRs or modulating G-proteins involved in adenosine-CFTR regulation system and epithelial Na channel function [12]. Complement 5a receptor1 (C5aR1), a member of GPCR family, has recently been proposed to be involved in COVID-19 pathogenesis [13]. GPCR4, which regulates vascular permeability and leukocyte recruitment, has been hypothesized to play a part in SARS-CoV2 infection [14].
In this article the role of GPCRs in the body and in COVID-19 are discussed.

1. Quitterer, U. and S. AbdAlla, Discovery of pathologic GPCR aggregation. Frontiers in medicine, 2019. 6: p. 9.
2. Zalewska, M., M. Siara, and W. Sajewicz, G protein-coupled receptors: abnormalities in signal transmission, disease states and pharmacotherapy. Acta Pol Pharm, 2014. 71(2): p. 229-243.
3. Rajagopal, S., K. Rajagopal, and R.J. Lefkowitz, Teaching old receptors new tricks: biasing seven-transmembrane receptors. Nature reviews Drug discovery, 2010. 9(5): p. 373-386.
4. Zhang, X.C., et al., Proton transfer-mediated GPCR activation. Protein & cell, 2015. 6(1): p. 12-17.
5. Walsh, C.T., D. Stupack, and J.H. Brown, G Protein–Coupled Receptors Go Extracellular: RhoA Integrates the Integrins. Molecular interventions, 2008. 8(4): p. 165.
6. Tilley, D.G., G protein–dependent and G protein–independent signaling pathways and their impact on cardiac function. Circulation research, 2011. 109(2): p. 217-230.
7. Peterson, Y.K. and L.M. Luttrell, The diverse roles of arrestin scaffolds in G protein–coupled receptor signaling. Pharmacological reviews, 2017. 69(3): p. 256-297.
8. Nejat, R. and A.S. Sadr, Are losartan and imatinib effective against SARS-CoV2 pathogenesis? A pathophysiologic-based in silico study. In silico pharmacology, 2021. 9(1): p. 1-22.
9. Magnani, F., et al., Electronic sculpting of ligand-GPCR subtype selectivity: the case of angiotensin II. ACS chemical biology, 2014. 9(7): p. 1420-1425.
10. Santos, R.A., et al., Angiotensin-(1–7) is an endogenous ligand for the G protein-coupled receptor Mas. Proceedings of the National Academy of Sciences, 2003. 100(14): p. 8258-8263.
11. Manglik, A., et al., β-Arrestin–Biased Angiotensin II Receptor Agonists for COVID-19. Circulation, 2020. 142(4): p. 318-320.
12. Hameid, R.A., et al., SARS-CoV-2 may hijack GPCR signaling pathways to dysregulate lung ion and fluid transport. American Physiological Society Rockville, MD.
13. Carvelli, J., et al., Association of COVID-19 inflammation with activation of the C5a–C5aR1 axis. Nature, 2020: p. 1-5.
14. Yang, L.V., et al., Can GPR4 Be a Potential Therapeutic Target for COVID-19? Frontiers in medicine, 2021. 7: p. 1150.

  • Open access
  • 88 Reads
, , , ,

There is a growing interest on dehydroacetic acid DHA derivatives compounds in recent years, due to an establish antibacterial, antifungal, anti-inflammatory and anticancer activities. Several researches were performed on ligand precursor and transition metal complexes derivatives.

Efficient and easy access to a transition metal chelates series with acid DHA as starting materials is reported, the obtained compounds were fully characterized by MP, UV-Vis and FT-IR spectroscopy, several in vitro biological tests were also performed on obtained metal chelates to explore its therapeutically potential in order to continue further investigations and exploring it as new target drugs. In this case, enzymatic activity: as urease inhibitors and antioxidant activities: ABTS free radical scavenging activity, β-carotène linoleic acid bleaching activity, Ferrous ions binding effect, Copper and ferrous chelating activity, gave good values of IC50 for all studied complexes 1-4 in range of 8,20 ±0,39-10,62 ±0,01 μg/mL for urease inhibiting test better than DHA and used standard Thiourea (IC50=11,57±0,68 μg/mL), interesting results are also obtained for compound 2 in ability of chelating ferrous ions with an IC50=14,53±0,92 μg/mL, comparing with tested standard EDTA (CI50=8,80±0,47 μg/mL), for all cited applications complex 4 is mostly a hit, while antimicrobial activity gave better results with free ligand DHA, discussion on molecular structure and predicted structure activity relationship will be given.

  • Open access
  • 84 Reads
Structural and biological evaluation of novel multi-target compound with potential application in the treatment of schizophrenia

In the process of searching for novel compounds with antipsychotic properties, structure-based virtual screening was conducted [1]. Among found dopamine D2 receptor antagonists, the compound D2AAK3 with 115 nM affinity for D2 receptor was identified. It also shows nanomolar or low micromolar affinity for D1, D3, 5-HT1A, 5-HT2A and 5-HT7 receptors, what makes it a good candidate for a multi-target drug. Interactions of D2AAK3 with its molecular targets at the molecular level were studied in silico by performing homology modeling, molecular docking and molecular dynamics. The main contact of D2AAK3 with all studied receptors is the electrostatic interaction between the proton attached to the nitrogen atom of the ligand and the conserved Asp(3.32), what is typical for orthosteric binding mode in aminergic GPCRs. Behavioral studies [2] performed for D2AAK3 revealed that it decreases amphetamine-induced hyperactivity measured as spontaneous locomotor activity in mice, improves memory consolidation after acute treatment in passive avoidance test and exhibits anxiogenic activity 30 minutes after acute treatment in mice in elevated plus maze (this effect was reversed 60 minutes after administration of D2AAK3). Further optimization of reported compound, toward obtaining molecule with properties resembling atypical antipsychotics, will be conducted.


  1. Kaczor AA, Silva AG, Loza MI, Kolb P, Castro M, Poso A (2016) ChemMedChem 11:718-729.
  2. Kaczor AA, Targowska-Duda KM, Budzyńska B, Biała G, Silva AG, Castro M (2016) Neurochemistry International 96:84-99.
  • Open access
  • 88 Reads
Molecular docking study on the interaction of Rhodopsin-like receptor with tetra-coordinated gold(III) complex

The pharmacologic properties of gold compounds have been known since the end of the 19th century. In the last decade, gold complexes have received increased attention due to the variety of their applications. Rhodopsin-like receptors are a family of proteins that belong to the largest group of G protein-coupled receptors (GPCRs).

In this paper, the molecular interactions between active binding sites of the Rhodopsin-like receptor (RLR) and synthesized gold(III) complex ([Au(DPP)Cl2]+ where DPP=4,7-diphenyl-1,10-phenanthroline) were investigated by molecular docking simulations. The crystal structure of investigated receptor RLR (PDB ID: 4A4M) was extracted from RCSB Protein Data Bank in PDB format. The native bound ligand (11-cis-retinal) was extracted from the receptor and binding pocket analysis was performed. Re-docking was performed with the gold(III) complex to generate the same docking pose as found in the co-crystallized form of the receptor.

The binding energy of the gold(III) complex to RLR was found to be -35.35 kJ/mol, as opposed to 11-cis-retinal which of about -40.5 kJ/mol. The obtained results revealed that gold(III) complex binds at the same binding pockets to RLR, as well as a native bound ligand, by weak non-covalent interactions. The most prominent interactions are hydrogen bonds, alkyl-π, and π-π interactions. The preliminary results suggest that the gold(III) complex showed good binding affinity against RLR, as well as a native bound ligand, 11-cis-retinal, as evident from the free binding energy (ΔGbind in kJ/mol).

  • Open access
  • 89 Reads
β2-adrenergic receptor polymorphism in intracellular signalling pathways

Research on the cognition of the human genome resulted in the publication of human DNA sequences at the beginning of the 21st century. Thanks to these discoveries, it became possible to learn the location, sequence and mutation of many genes that play an important role in the pathogenesis of certain diseases and are the cause of individual sensitivity to the drug administered [1].

The β2-adrenergic receptor belongs to an important family of G-protein coupled receptors (GPCRs). β2-AR is an extremely important molecular target for drugs used in the treatment of asthma and heart failure. β2-AR is encoded by the ADRB2 gene present in many polymorphs, differing in the types of amino acid residues. Single nucleotide polymorphism (SNP) can lead to differences in the structure and action of the gene-encoded protein, which in turn affects how the protein interacts with the drug molecule, the activation of the receptor, and consequently the course of the disease and the success of the therapy used [1].

Literature data indicate the relationship of polymorphism with the exacerbated course of many chronic diseases such as circulatory failure, arterial hypertension with concomitant obesity, asthma. Receptor polymorphism may also influence the variable response to drugs used, as well as the faster development of tolerance to them [1].

Since the presence of polymorphism may result in differences in intracellular signalling, the present research determined differences in the activation level of intracellular signalling pathways for selected agonists.

  1. Litonjua AA, Gong L, Duan QL, i in. (2010). Very important pharmacogene summary ADRB2. Pharmacogenetics and Genomics, 20(1):64–69.
  • Open access
  • 89 Reads
Rhythmically-Enhanced Music as Analgesic for Chronic Pain: a Pilot Non-Controlled Observational Study

Chronic pain changes brain connectivity, brainwave organization, and volume, often resulting in disability, anxiety and depression. Opioid pain relievers impair function, with risk of addiction. Music analgesia research suggests that music for long-term analgesia includes slow tempo, pleasantness, and self-choice. We hypothesized that volunteers listening to self-chosen music with beats embedded, for ½ hour twice a day, could show brainwave entrainment (BWE) at frequencies of healthy descending pain modulatory system (DPMS). Over time such BWE may change brain activity, and restore organization in DPMS altered by chronic pain.

Volunteers with chronic pain > 1year participated in a study of 4 weeks of listening to one half hour of prepared music twice a day, and four weeks of non-listening, reporting pain and analgesic use during the study. Assessments used visual analog scale (VAS) and 0-10 numerical pain scores (NPS), medication types and dosage.

A mobile app provided a menu of 27 half-hour pieces of music in several genres to choose from. Isochronic beats were embedded in the music with tempo, key, and isochronic pulsed theta frequencies proportional to each other, to enhance the brain’s perception of rhythmic patterns and harmonics.

Results: Mean NPS showed a 26% reduction (p = .018). More significantly, mean medication dosage declined by over 60% (p = .008). Larger populations and longer trial periods are needed to determine the efficacy of music vs the music with brainwave beats.

  • Open access
  • 69 Reads
The biopsychological indicators of age significantly influence on the severity of Covid-19

Objectives: to investigate the effect of biopsychological age indicators on the severity of Covid-19 disease in adults of different age groups of the Russian Federation population during the 2020 epidemic. Methods: comprehensive studies and questionnaires were carried out (Longitudinal study). The indicators of biopsychological age were measured in the middle of 2019, and in the middle of 2020. Additionally, in the middle and end of 2020, the number of cases, the severity of the disease and its outcome were assessed. 447 people aged 35-70 years (women 306) were examined. Group 1 (working adults) - 239 people (155 women). Group 2 (risk group) - unemployed pensioners with chronic diseases - 208 people (151 women). The indicators of biological age, self-assessment of health, indicators of subjective psychological age were evaluated. The significance of biopsychological age indicators influence on disease severity was calculated by Anova analysis.

Results. In mid-2020 (during quarantine), an increase in biological age and biological aging index was observed in Group 1. For men - (by 3.9 - 8 years) P <0.05; for women, a slight increase (at the level of the trend); On the contrary, in group 2 there was no increase in the rate of biological aging during quarantine. According to the indicators of subjective psychological age, group 1 (working people) began to feel younger (by 3.3 - 7.2 years) P <0.05, but the expected retirement age did not change and remained below that established in Russia. The number of COVID-19 cases was: 0.2% in the middle of 2020 and 16.5% at the end of 2020. The influence of indicators of biopsychological age on the severity of the disease in group 1 was revealed. In women, biological age, relative biological aging, pulse pressure, self-assessment of diseases increased the severity of the disease. An increase in relative psychological aging, on the contrary, reduced the severity of the disease (p <0.05). Body weight, static balancing had no effect. In men, biological age, deterioration in self-esteem of diseases increased the severity of the disease, while relative psychological aging also decreased the severity of the disease. Blood pressure, time of breath holding on inspiration, relative biological aging, psychological age, static balancing did not affect the severity of symptoms of the disease in men. In contrary to our expectation, no any cases of the COVID-19 in group 2 (risk group) were observed.

Conclusions: Indicators of relative biological and psychological aging of an individual affect the development of the disease and its severity, while the combination of increase in relative biological aging and underestimated psychological age are the most dangerous and increase the probability of developing severe forms of Covid-19 (P <0.05). The identified indicators can point to special attention groups for intensive treatment and priority vaccination during the COVID-19 epidemic.

This work was supported by Russian Science Foundation, No. 19-18-00058

  • Open access
  • 104 Reads
The study of natural compounds as antidepressants by bioinformatics methods

According to the World Health Organization, the neuropsychiatric disorders pose an increasingly greater burden on health, society and economy of countries. Currently there are strategies to prevent some of these disorders and there are treatments or means to alleviate their symptoms. In the case of depression, the medication consists of antidepressant drugs. Such drugs can also be used in other conditions like anxiety, pain or insomnia. A shortcoming of the currently used antidepressants is the occurrence of side effects that sometimes are unbearable for the patient. In this respect, a promising direction is the usage of medicinal plants. Plant parts are rich in phytochemicals that could be beneficial in mental disorders by acting on various targets. Here we investigated the antidepressant effect of ten natural compounds from sage, mint and citrus. The biological activity of these compounds was investigated by calculating ki values and affinities for dopamine receptor D2, serotonin transporter (SERT) and 5-hydroxytryptamine receptor 1A (5HT1A) using Almond-Pentacle software. Our results showed that resveratrol and rutin could be efficient antidepressants.

Acknowledgments. The study was supported by UEFISCDI through the projects PN-III-P2-2.1-PED2019-1471 “New biocompatible shagaol and curcuminoid-like products used as adjuvantes in cancer radiotherapy” and PN-III-P1-1.2-PCCDI-2017-0728 “Integrated project for the development of technologies dedicated to advanced medical treatments”.

  • Open access
  • 73 Reads
TCGA PanCanAtlas data analysis suggests multiple possibilities for personalized cancer therapy

Personalized cancer medicine holds promise for the future of cancer treatment. The key to success is the knowledge of exact molecular alterations that drive tumorigenesis in a given patient, so that a suitable targeted therapy can be selected. However, the extent of such alterations, i.e. number of various kinds of driver mutations per patient, is still not known. We have utilized the largest database of human cancer mutations – TCGA PanCanAtlas, multiple popular algorithms for cancer driver prediction and several custom scripts to estimate the number of various kinds of driver mutations in primary tumors. We have found that there are on average 19.6 driver mutations per patient’s tumor, of which 2.4 are hyperactivating SNA mutations in oncogenes, 9.2 are CNA amplifications of oncogenes, 0.6 have both in the same oncogene, 0.2 are homozygous inactivating SNA mutations in tumor suppressors, 1.1 have inactivating SNA mutation in one allele and CNA deletion in the other allele of a tumor suppressor, 1.5 are driver chromosome losses, 2 are driver chromosome gains, 1 is driver chromosome arm loss, and 1.6 are driver chromosome arm gains. The number of driver mutations per tumor gradually increased with age, from 12.5 for <25 y.o. to 23.6 for >85 y.o. There was no big difference between genders (19.9 in males vs 19.2 in females). The number of driver mutations per tumor varied strongly between cancer types, from 1.5 in thyroid carcinoma to 43 in lung squamous cell carcinoma. Overall, our results provide valuable insights into the extent of driver alterations in tumors and suggest that multiple possibilities to choose a suitable targeted therapy exist in each patient.

  • Open access
  • 196 Reads

Cancer Stem Cells and Somatic Stem Cells as Potential New Drug Targets, and Prognosis Markers, and Therapy Efficacy Predictors in Breast Cancer Treatment

Breast cancer (BC) is one of the leading causes of cancer death in women. Thus, the search for drug targets, markers of disease prognosis, and more efficient treatment options is relevant. We have conducted a pilot study including patients with luminal B stage breast cancer IIA-IIIB (T1-3N0-3M0), triple-negative BC, and HER+ BC (age range: 28 to 66 years). The control group consisted of healthy women of similar age. Presence and frequency of various populations of cancer stem cells (CSC) and somatic stem cells (e.g., hematopoietic stem cells, endothelial progenitor cells, and epithelial precursors) were assessed in the blood from the cubital vein, breast tumor tissue, and tissue adjacent to the tumor. Moreover, the sensitivity of CSC and somatic stem cells to drugs used in chemotherapy was assessed in vitro.

Our results suggest that patients with BC can be divided into two distinct groups based on the frequency of aldehyde dehydrogenase positive cells (ALDH+ cells) in the assessed tissues (ALDHhi and ALDHlow). For each group of patients, different cellular biomarkers for the prognosis of metastasis are proposed. In patients within the ALDHhi group, potential biomarkers of metastasis are HSCs, CSC (CD227+CD44+CD24-), and epithelial tumor cells (CD44+CD24CD49f+). In contrast, epithelial tumor cells (CD326+CD44+CD24) and breast mesenchymal stem cells (CD326CD49f+) are proposed as cellular metastasis biomarkers in ALDHlow patients. We have shown that these cells are resistant to cytostatics and can thus act as potential contributors to tumor progression and formation of metastases. Since these cell types are present in the patient circulation, we hypothesize that they are potential markers of the disease prognosis and predictors of the efficacy of the treatment. To increase the effectiveness of chemotherapy, we propose to evaluating the efficacy of cytostatics in vitro using biopsy material.

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