A Comprehensive Overview of Globally Approved JAK Inhibitors.

Janus kinase (JAK) is a family of cytoplasmic non-receptor tyrosine kinases that includes four members, namely JAK1, JAK2, JAK3, and TYK2. The JAKs transduce cytokine signaling through the JAK-STAT pathway, which regulates the transcription of several genes involved in inflammatory, immune, and cancer conditions. Targeting the JAK family kinases with small-molecule inhibitors has proved to be effective in the treatment of different types of diseases. In the current review, eleven of the JAK inhibitors that received approval for clinical use have been discussed. These drugs are abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, and upadacitinib. The aim of the current review was to provide an integrated overview of the chemical and pharmacological data of the globally approved JAK inhibitors. The synthetic routes of the eleven drugs were described. In addition, their inhibitory activities against different kinases and their pharmacological uses have also been explained. Moreover, their crystal structures with different kinases were summarized, with a primary focus on their binding modes and interactions. The proposed metabolic pathways and metabolites of these drugs were also illustrated. To sum up, the data in the current review could help in the design of new JAK inhibitors with potential therapeutic benefits in inflammatory and autoimmune diseases.

Adsorption of Molnupiravir anti-COVID-19 drug over B12N12 and Al12N12 nanocarriers: a DFT study.

The potentiality of B12N12 and Al12N12 nanocarriers to adsorb Molnupiravir anti-COVID-19 drug, for the first time, was herein elucidated using a series of quantum mechanical calculations. Density function theory (DFT) was systematically utilized. Interaction (Eint) and adsorption (Eads) energies showed higher negative values for Molnupiravir···Al12N12 complexes compared with Molnupiravir···B12N12 analogs. Symmetry-adapted perturbation theory (SAPT) results proclaimed that the adsorption process was predominated by electrostatic forces. Notably, the alterations in the distributions of the molecular orbitals ensured that the B12N12 and Al12N12 nanocarriers were efficient candidates for delivering the Molnupiravir drug. From the thermodynamic perspective, the adsorption process of Molnupiravir drug over B12N12 and Al12N12 nanocarriers had spontaneous and exothermic nature. The ESP, QTAIM, NCI, and DOS observations exposed the tendency of BN and Al12N12 to adsorb the Molnupiravir drug. Overall, these findings proposed that the B12N12 and Al12N12 nanocarriers are efficient aspirants for the development of the Molnupiravir anti-COVID-19 drug delivery process.Communicated by Ramaswamy H. Sarma.

Chetomin, a SARS-CoV-2 3C-like Protease (3CLpro) Inhibitor: In Silico Screening, Enzyme Docking, Molecular Dynamics and Pharmacokinetics Analysis.

The emergence of the Coronavirus Disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to over 6 million deaths. The 3C-like protease (3CLpro) enzyme of the SARS-CoV-2 virus is an attractive druggable target for exploring therapeutic drug candidates to combat COVID-19 due to its key function in viral replication. Marine natural products (MNPs) have attracted considerable attention as alternative sources of antiviral drug candidates. In looking for potential 3CLpro inhibitors, the MNP database (>14,000 molecules) was virtually screened against 3CLpro with the assistance of molecular docking computations. The performance of AutoDock and OEDocking software in anticipating the ligand-3CLpro binding mode was first validated according to the available experimental data. Based on the docking scores, the most potent MNPs were further subjected to molecular dynamics (MD) simulations, and the binding affinities of those molecules were computed using the MM-GBSA approach. According to MM-GBSA//200 ns MD simulations, chetomin (UMHMNP1403367) exhibited a higher binding affinity against 3CLpro than XF7, with ΔGbinding values of −55.5 and −43.7 kcal/mol, respectively. The steadiness and tightness of chetomin with 3CLpro were evaluated, revealing the high stabilization of chetomin (UMHMNP1403367) inside the binding pocket of 3CLpro throughout 200 ns MD simulations. The physicochemical and pharmacokinetic features of chetomin were also predicted, and the oral bioavailability of chetomin was demonstrated. Furthermore, the potentiality of chetomin analogues −namely, chetomin A-D− as 3CLpro inhibitors was investigated. These results warrant further in vivo and in vitro assays of chetomin (UMHMNP1403367) as a promising anti-COVID-19 drug candidate.

Investigation of Aluminum Nitride Nanocarrier for Drug Delivery Process of Favipiravir: A DFT Study

The tendency of Al12N12 nanocarrier toward adsorbing Favipiravir (FPV), an anti-COVID-19 drug, was obviously unveiled within five configurations via O∙∙∙, N∙∙∙, and F∙∙∙Al interactions. The geometric and electronic properties of Al12N12 nanocarrier, FPV drug, and FPV∙∙∙Al12N12 complexes were thoroughly evaluated in gas and water phases. Among all the studied complexes, the most preferential negative interaction and adsorption energies were ascribed to configuration A with values of –51.11 and –38.82 kcal/mol, respectively. Symmetry-adapted perturbation theory (SAPT) analysis addressed the electrostatic force as the most dominant energetic component beyond the occurrence of the adsorption process within the studied complexes. Apparently, significant changes were noticed within the distributions of the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) of the FPV and Al12N12 before and after the adsorption process. Noticeable increments in softness and decrement in hardness were also observed after the adsorption process, ensuring strong interactions within the studied complexes. The adsorption process was also studied in the water phase. The negative values of thermodynamic parameters ensured that the adsorption process had spontaneity and exothermic nature within almost all the studied complexes. Further favorability of the adsorption of FPV was noticed over the surface of Al12N12 nanocarrier compared to the B12N12 analog. For the FPV∙∙∙B12N12 complexes, unfavorable Gibbs free energy (ΔG) values along with neglected recovery time values revealed the bare tendency of the B12N12 nanocarrier toward adsorbing FPV drug. The findings of the presented study will serve as a springboard for further research into Al12N12 nanocarrier as well as the delivery of the FPV anti-COVID-19 drug.

Eryngium creticum L.: Chemical Characterization, SARS-CoV-2 Inhibitory Activity, and In Silico Study.

Phytochemical investigation of Eryngium creticum L. has resulted in isolation of five compounds, including four compounds that are reported from the plant for the first time. Compound 1 was identified as (E)-rosmarinic acid, meanwhile, compound 2 was isolated as an (E/Z)-rosmarinic acid mixture. Interestingly, the E/Z-isomeric mixture was about 4 times as active as the single E-isomer toward the severe acute respiratory syndrome coronavirus 2 3-chymotrypsin-like protease (3CLpro), IC50 = 6.062 and 25.75 µM, respectively. Utilizing combined molecular docking and molecular dynamics (MD) techniques, the binding affinities and features of the isolated compounds were evaluated against 3CLpro. Compound 2Z demonstrated a higher binding affinity for 3CLpro than 2E , with docking scores of -8.9 and -8.5 kcal/mol and MM-GBSA/150 ns MD binding energies of -26.5 and -22.1 kcal/mol, respectively. This justifies the superior activity of the E/Z-isomeric mixture versus the single E-isomer. Structural and energetic analyses revealed the stability of 2Z and 2E compared to the reference HIV-1 protease inhibitor, lopinavir. Besides, DFT calculations demonstrated the more energetic stability of 2E compared to 2Z , which justifies the difficulty in isolating the Z-isomer in a pure form, where it readily isomerizes to the E-isomer.

Exploring Toxins for Hunting SARS-CoV-2 Main Protease Inhibitors: Molecular Docking, Molecular Dynamics, Pharmacokinetic Properties, and Reactome Study.

The main protease (Mpro) is a potential druggable target in SARS-CoV-2 replication. Herein, an in silico study was conducted to mine for Mpro inhibitors from toxin sources. A toxin and toxin-target database (T3DB) was virtually screened for inhibitor activity towards the Mpro enzyme utilizing molecular docking calculations. Promising toxins were subsequently characterized using a combination of molecular dynamics (MD) simulations and molecular mechanics-generalized Born surface area (MM-GBSA) binding energy estimations. According to the MM-GBSA binding energies over 200 ns MD simulations, three toxins-namely philanthotoxin (T3D2489), azaspiracid (T3D2672), and taziprinone (T3D2378)-demonstrated higher binding affinities against SARS-CoV-2 Mpro than the co-crystalized inhibitor XF7 with MM-GBSA binding energies of -58.9, -55.9, -50.1, and -43.7 kcal/mol, respectively. The molecular network analyses showed that philanthotoxin provides a ligand lead using the STRING database, which includes the biochemical top 20 signaling genes CTSB, CTSL, and CTSK. Ultimately, pathway enrichment analysis (PEA) and Reactome mining results revealed that philanthotoxin could prevent severe lung injury in COVID-19 patients through the remodeling of interleukins (IL-4 and IL-13) and the matrix metalloproteinases (MMPs). These findings have identified that philanthotoxin-a venom of the Egyptian solitary wasp-holds promise as a potential Mpro inhibitor and warrants further in vitro/in vivo validation.

A Proposed Modified SEIQR Epidemic Model to Analyze the COVID-19 Spreading in Saudi Arabia

The key aim of this paper is to construct a modified version of the SEIQR essential disease dynamics model for the COVID-19 emergence. The modified SEIQR pandemic model takes a groundbreaking approach to evaluate and monitor the COVID-19 epidemic. The complex studies presented in this paper are based on real-world data from Saudi Arabia. A reproduction number and a systematic stability analysis are included in the new version of SEIQR model dynamics. Using the Jacobian linearization process, we can obtain the domain of the solution and the state of equilibrium based on the modified SEIQR model. The equilibrium and its importance have been identified, and the disease-free stability of the equilibrium has been investigated. The reproduction number was calculated using internal metrics, and the global stability of the current model's equilibrium was demonstrated using Lyapunov's stability theorem. To see how well the SEIQR proposed model went, it was compared to real COVID-19 spread data in Saudi Arabia. According to the results, the new SEIQR proposed model is a good match for researching the spread of epidemics like COVID-19. In the end, we presented an optimal protocol to prevent the dissemination of COVID-19. Staying at home and transporting sick people as far as possible to a safe region is the most effective strategy to prevent COVID-19 spread. It is critical to offer infected people safe and effective treatment, as well as antibiotics and nutrients to non-affected people. To detect confirmed infections, we must provide more effective and reliable diagnostic methods. Furthermore, increasing understanding of how to recognize the disease, its symptoms, and how to confirm the infection.

Study on the SEIQR model and applying the epidemiological rates of COVID-19 epidemic spread in Saudi Arabia.

This article attempts to establish a mathematical epidemic model for the outbreak of the new COVID-19 coronavirus. A new consideration for evaluating and controlling the COVID-19 outbreak will be constructed based on the SEIQR Pandemic Model. In this paper, the real data of COVID-19 spread in Saudi Arabia has been used for the mathematical model and dynamic analyses. Including the new reproductive number and detailed stability analysis, the dynamics of the proposed SEIQR model have been applied. The local sensitivity of the reproduction number has been analyzed. The domain of solution and equilibrium based on the SEIQR model have been proved using a Jacobian linearization process. The state of equilibrium and its significance have been proved, and a study of the integrity of the disease-free equilibrium has been carried out. The Lyapunov stability theorem demonstrated the global stability of the current model equilibrium. The SEIQR model has been numerically validated and projected by contrasting the results from the SEIQR model with the actual COVID-19 spread data in Saudi Arabia. The result of this paper shows that the SEIQR model is a model that is effective in analyzing epidemic spread, such as COVID-19. At the end of the study, we have implemented the protocol which helped the Saudi population to stop the spread of COVID-19 rapidly.

Rutin and flavone analogs as prospective SARS-CoV-2 main protease inhibitors: In silico drug discovery study.

Coronavirus disease 2019 (COVID-19) is a new pandemic characterized by quick spreading and illness of the respiratory system. To date, there is no specific therapy for Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2). Flavonoids, especially rutin, have attracted considerable interest as a prospective SARS-CoV-2 main protease (Mpro) inhibitor. In this study, a database containing 2017 flavone analogs was prepared and screened against SARS-CoV-2 Mpro using the molecular docking technique. According to the results, 371 flavone analogs exhibited good potency towards Mpro with docking scores less than -9.0 kcal/mol. Molecular dynamics (MD) simulations, followed by molecular mechanics-generalized Born surface area (MM/GBSA) binding energy calculations, were performed for the top potent analogs in complex with Mpro. Compared to rutin, PubChem-129-716-607 and PubChem-885-071-27 showed better binding affinities against SARS-CoV-2 Mpro over 150 ns MD course with ΔGbinding values of -69.0 and -68.1 kcal/mol, respectively. Structural and energetic analyses demonstrated high stability of the identified analogs inside the SARS-CoV-2 Mpro active site over 150 ns MD simulations. The oral bioavailabilities of probable SARS-CoV-2 Mpro inhibitors were underpinned using drug-likeness parameters. A comparison of the binding affinities demonstrated that the MM/GBSA binding energies of the identified flavone analogs were approximately three and two times less than those of lopinavir and baicalein, respectively. In conclusion, PubChem-129-716-607 and PubChem-885-071-27 are promising anti-COVID-19 drug candidates that warrant further clinical investigations.

A modified SEIR model applied to the data of COVID-19 spread in Saudi Arabia.

The Susceptible-Exposed-Infectious-Recovered (SEIR) model is an established and appropriate approach in many countries to ascertain the spread of the coronavirus disease 2019 (COVID-19) epidemic. We wished to create a new COVID-19 model to be suitable for patients in any country. In this work, a modified SEIR model was constructed. We used the real data of COVID-19 spread in Saudi Arabia for statistical analyses and complex analyses. The reproduction number and detailed review of stability demonstrated the complexities of our proposed SEIR model. The solution and equilibrium condition were explored based on Jacobian's linearization approach to the proposed SEIR model. The state of equilibrium was demonstrated, and a stability study was conducted in the disease-free environment. The reproduction number was measured sensitively against its internal parameters. Using the Lyapunov principle of equilibrium, the overall consistency of balance of our model was demonstrated. Findings using the SEIR model and observed outcomes due to COVID-19 spread in Saudi Arabia were compared. The modified SEIR model could enable successful analyses of the spread of epidemics such as COVID-19. An "ideal protocol" comprised essential steps to help Saudi Arabia decelerate COVID-19 spread. The most important aspects are to stay at home as much as possible and for infected people to remain in an isolated zone or secure area.

Synthesis of potentially new schiff bases of N-substituted-2-quinolonylacetohydrazides as anti-COVID-19 agents.

We report herein a new series of synthesized N-substituted-2-quinolonylacetohydrazides aiming to evaluate their activity towards SARS-CoV-2. The structures of the obtained products were fully confirmed by NMR, mass, IR spectra and elemental analysis as well. Molecular docking calculations showed that most of the tested compounds possessed good binding affinity to the SARS-CoV-2 main protease (Mpro) comparable toRemdesivir.

A new dynamical modeling SEIR with global analysis applied to the real data of spreading COVID-19 in Saudi Arabia.

SEIR model is a widely used and acceptable model to distinguish the outbreak of the COVID-19 epidemic in many countries. In the current work, a new proposed SEIR model as a mathematical model for the outbreak of novel coronaviruses COVID-19 will be constructed. The new proposed SEIR pandemic model provides a new vision for evaluations and management of the epidemic of COVID-19 infection. For mathematical modeling and dynamic analyses, this paper uses the real data of spreading COVID-19 in Saudi Arabia. The dynamics of the proposed SEIR model are presented with the reproduction number and the extensive stability analysis. We discussed the domain of the solution and equilibrium situation based on the proposed SEIR model by using Jacobian's method of linearization. The condition of equilibrium and its uniqueness has been proved, and the stability analysis of disease-free equilibrium has been introduced. A sensitivity analysis of the reproduction number against its internal parameters has been done. The global stability of the equilibrium of this model has been proved by using Lyapunov's Stability theorem. A numerical verification and predictions of the proposed SEIR model have been made with comparing the results based on the SEIR model and the real data due to the spreading of the COVID-19 in Saudi Arabia. The proposed SEIR model is a successful model to analyze the spreading of epidemics like COVID-19. This work introduces the ideal protocol, which can help the Saudi population to breakdown spreading COVID-19 in a fast way.