RESUMEN
BACKGROUND: Coronavirus disease 2019 (COVID-19) has demonstrated several clinical manifestations which include not only respiratory system issues but also liver, kidney, and other organ injuries. One of these abnormalities is coagulopathies, including thrombosis and disseminated intravascular coagulation. Because of this, the administration of low molecular weight heparin is required for patients that need to be hospitalized. In addition, Remdesivir is an antiviral that was used against Middle East Acute Respiratory Syndrome, Ebola, Acute Respiratory Syndrome, and other diseases, showing satisfactory results on recovery. Besides, there is evidence suggesting that this medication can provide a better prognosis for patients with COVID-19. AIM: To investigate in silico the interaction between Remdesivir and clotting factors, pursuing a possibility of using it as medicine. METHODS: In this in silico study, the 3D structures of angiotensin-converting enzyme 2 (ACE2), Factor I (fibrinogen), Factor II (prothrombin), Factor III (thromboplastin), Factor V (proaccelerin), Factor VII (proconvertin), Factor VIII (antihemophilic factor A), Factor IX (antihemophilic factor B), Factor X (Stuart-Prower factor), and Factor XI (precursor of thromboplastin (these structures are technically called receptors) were selected from the Protein Data Bank. The structures of the antivirals Remdesivir and Osetalmivir (these structures are called ligands) were selected from the PubChem database, while the structure of Atazanavir was selected from the ZINC database. The software AutoDock Tools (ADT) was used to prepare the receptors for molecular docking. Ions, peptides, water molecules, and other ones were removed from each ligand, and then, hydrogen atoms were added to the structures. The grid box was delimited and calculated using the same software ADT. A physiological environment with pH 7.4 is needed to make the ligands interact with the receptors, and still the software Marvin sketch® (ChemAxon®) was used to forecast the protonation state. To perform molecular docking, ADT and Vina software was connected. Using PyMol® software and Discovery studio® software from BIOVIA, it was possible to analyze the amino acid residues from receptors that were involved in the interactions with the ligands. Ligand tortions, atoms that participated in the interactions, and the type, strength, and duration of the interactions were also analyzed using those software. RESULTS: Molecular docking analysis showed that Remdesivir and ACE2 had an affinity energy of -8.8 kcal/moL, forming a complex with eight hydrogen bonds involving seven atoms of Remdesivir and five amino acid residues of ACE2. Remdesivir and prothrombin had an interaction with six hydrogen bonds involving atoms of the drug and five amino acid residues of the clotting factor. Similar to that, Remdesivir and thromboplastin presented interactions via seven hydrogen bonds involving five atoms of the drug and four residues of the clotting factor. While Remdesivir and Factor V established a complex with seven hydrogen bonds between six antiviral atoms and six amino acid residues from the factor, and Factor VII connected with the drug by four hydrogen bonds, which involved three atoms of the drug and three residues of amino acids of the factor. The complex between Remdesivir and Factor IX formed an interaction via 11 hydrophilic bonds with seven atoms of the drug and seven residues of the clotting factor, plus one electrostatic bond and three hydrophobic interactions. Factor X and Remdesivir had an affinity energy of -9.6 kcal/moL, and the complex presented 10 hydrogen bonds and 14 different hydrophobic interactions which involved nine atoms of the drug and 16 amino acid residues of the clotting factor. The interaction between Remdesivir and Factor XI formed five hydrogen bonds involving five amino acid residues of the clotting factor and five of the antiviral atoms. CONCLUSION: Because of the in silico significant affinity, Remdesivir possibly could act in the severe acute respiratory syndrome coronavirus 2 infection blockade by interacting with ACE2 and concomitantly act in the modulation of the coagulation cascade preventing the hypercoagulable state.
RESUMEN
BACKGROUND: Inflammatory bowel diseases (IBD) are a worldwide health problem and mainly affect young people, consequently affecting the workforce. Available treatments are often associated with side effects, and new therapeutic options are needed. For centuries, plants have represented important substrates in the field of drug development. Lafoensia pacari (L. pacari) is a plant whose pharmaceutical potential has been described, and may have biological activity relevant to the treatment of IBD symptoms. AIM: To investigate the activity of keto-alcoholic extracts of L. pacari with respect to ameliorating the inflammatory and nociceptive symptoms of acute experimental colitis in mice. METHODS: Keto-alcoholic extracts of L. pacari leaves and bark were administered to male and female Swiss mice weighing 25 g to 30 g (n = 8 male mice and n = 8 female mice). The effect of these extracts was observed in an acetic acid-induced acute experimental model of colitis with regard to antinociception/analgesia and inflammatory tissue damage. Recorded macroscopic indices included the Wallace score and the colon weight obtained using a precision scale. Mechanical hyperalgesia was determined using an electronic analgesimeter. Behavior related to overt pain was determined by quantifying the number of writhing instances within 20 min of administration of acetic acid. Molecular docking was performed using human and murine cyclooxygenase-2 (COX-2) with 3 flavonoids (ellagic acid, kaempferol, and quercetin) on the AutoDock Vina software. Analysis of variance followed by Tukey's posttest was used with P < 0.05 indicating significance. RESULTS: In this murine model of colitis, administration of extracts from L. pacari ameliorated acetic acid-induced writhing and colitis-associated inflammatory pain. These improvements may be attributable to the reduction in edema, inflammation (e.g., ulcers, hyperemia, and bowel wall damage), and the intensity of abdominal hyperalgesia. The keto-alcoholic extracts of L. pacari leaves and bark administered at a dose of either 100 mg/kg or 300 mg/kg significantly reduced the number of writhing events when compared to the negative control (P < 0.05). Additionally, extracts of L. pacari bark also performed better than Dipyrone. Leaf extracts administered at 10 mg/kg, 30 mg/kg, and 100 mg/kg and bark extracts administered at 30 mg/kg significantly reduced or prevented the development of edema in the colon of treated mice, while mesalazine did not. Moreover, using molecular docking, we observed that the flavonoids present in L. pacari extracts bind to COX-2, an event not unique to ellagic acid. CONCLUSION: The results of this study demonstrate a potential novel application of L. pacari extracts for the reduction of inflammation and promotion of antinociception/analgesia as demonstrated by our findings in a murine model of colitis. These findings were also corroborated by in silico analyses, and suggest that L. pacari extracts may be a promising therapeutic agent in the treatment of IBD.