Abstract In 2022, a global outbreak of Mpox (formerly monkeypox) occurred in various countries across Europe and America and rapidly spread to more than 100 countries and regions. The World Health Organization declared the outbreak to be a public health emergency of international concern due to the rapid spread of the Mpox virus. Consequently, nations intensified their efforts to explore treatment strategies aimed at combating the infection and its dissemination. Nevertheless, the available therapeutic options for Mpox virus infection remain limited. So far, only a few numbers of antiviral compounds have been approved by regulatory authorities. Given the high mutability of the Mpox virus, certain mutant strains have shown resistance to existing pharmaceutical interventions. This highlights the urgent need to develop novel antiviral drugs that can combat both drug resistance and the potential threat of bioterrorism. Currently, there is a lack of comprehensive literature on the pathophysiology and treatment of Mpox. To address this issue, we conducted a review covering the physiological and pathological processes of Mpox infection, summarizing the latest progress of anti-Mpox drugs. Our analysis encompasses approved drugs currently employed in clinical settings, as well as newly identified small-molecule compounds and antibody drugs displaying potential antiviral efficacy against Mpox. Furthermore, we have gained valuable insights from the process of Mpox drug development, including strategies for repurposing drugs, the discovery of drug targets driven by artificial intelligence, and preclinical drug development. The purpose of this review is to provide readers with a comprehensive overview of the current knowledge on Mpox. 

Mpox (formerly monkeypox): pathogenesis, prevention, and treatment

Carica papaya, commonly referred to as papaya, is a member of the Caricaceae family, boasting a diverse array of compounds and biomolecules, notably papain, with significant industrial and medicinal value. This comprehensive review meticulously examines the properties, extraction techniques, and pharmacological importance of papain, coupled with an exploration of the pharmacological activities inherent in C. papaya. Extensive research data from reputable sources such as Google Scholar, PubMed, Scopus, and Web of Science were scrutinized to collate pertinent information on the plant and its enzyme. Within C. papaya, a spectrum of bioactive compounds were identified, encompassing alkaloids, tannins, phenolics, flavonoids, saponins, terpenoids, sugars, glycosides, amino acids, steroids, and the pivotal enzyme papain. Papain extraction methods and their activity modulation in response to pH, temperature, and other physicochemical parameters were examined in detail. This review provides a nuanced analysis of papain, addressing both its pharmacological implications and potential side effects. Its far-reaching applications in the medical, industrial, and pharmaceutical sectors were meticulously discussed, unveiling its market potential. Furthermore, C. papaya emerged as a reservoir of pharmacological activities, exhibiting antioxidant properties, anti-cancer potential, wound healing capabilities, digestive disorder management, and anxiolytic effects. The research underscores the promising potential of C. papaya and papain for diverse biological applications, prompting a call for further studies to unlock their therapeutic benefits, particularly in the realm of public health. Looking ahead, continued advancements in drug development hold the key to unraveling the intricate bioactive components of papaya and its papain cysteine proteases. These insights are poised to catalyze their development and application, promising substantial contributions to the betterment of humanity. 

Therapeutic Benefits of Carica Papaya: A Review on its Pharmacological Activities and Characterization of Papain

Carboxylated chalcones and related flavonoids as inhibitors of xanthine oxidase

Identification of novel STAT3 inhibitors for liver fibrosis, using pharmacophore-based virtual screening, molecular docking, and biomolecular dynamics simulations

We synthesized fourteen benzimidazole-containing sulfonamide analogs (1–14), characterized them using methods including NMR and HR-EIMS. The synthesized analogs were then tested against the enzymes α-glucosidase and α-amylase showing IC50 values ranging from 9.20 ± 0.10 to 38.30 ± 0.40 μM (for α-glucosidase) and 5.20 ± 0.30 to 18.20 ± 0.30 μM (for α-amylase), all analogues show good inhibitory capability when compared to the reference medication acarbose (IC50 = 38.45 ± 0.80 & 11.12 ± 0.15 μM, respectively). The strongest inhibitor among the series for α-amylase analogues was 3 (IC50 = 5.20±0.30 μM), whereas the strongest inhibitor in the series for α-glucosidase was analog 6 (IC50 = 9.20 0.10 μM). All other analogs showed excellent potency against the α-glucosidase enzyme while in case of α-amylase analogs showed excellent to moderate potency. The structure-activity relationship was established for determining the increase/decrease in potency due to quantity, type, position, and electron-donating/withdrawing effects of the substituent/s on the phenyl ring. To demonstrate the binding interaction of the most potent analogues with the enzyme's active sites, a molecular docking research was performed. 

Synthesis, in vitro α-glucosidase, α-amylase inhibitory potentials and molecular docking study of benzimidazole bearing sulfonamide analogues

The new coronavirus SARS-COV-2, which emerged in late 2019 from Wuhan city of China was regarded as causing agent of the COVID-19 pandemic. The primary protease which is also known by various synonymous i.e., main protease, 3-Chymotrypsin-like protease (3CLPRO) has a vital role in the replication of the virus, which can be used as a potential drug target. The current study aimed to identify novel phytochemical therapeutics for 3CLPRO by machine learning-based virtual screening. A total of 4,000 phytochemicals were collected from deep literature surveys and various other sources. The 2D structures of these phytochemicals were retrieved from the PubChem database, and with the use of a molecular operating environment, 2D descriptors were calculated. Machine learning-based virtual screening was performed to predict the active phytochemicals against the SARS-CoV-2 3CLPRO. Random forest achieved 98% accuracy on the train and test set among the different machine learning algorithms. Random forest model was used to screen 4,000 phytochemicals which leads to the identification of 26 inhibitors against the 3CLPRO. These hits were then docked into the active site of 3CLPRO. Based on docking scores and protein-ligand interactions, MD simulations have been performed using 100 ns for the top 5 novel inhibitors, ivermectin, and the APO state of 3CLPRO. The post-dynamic analysis i.e,. Root means square deviation (RMSD), Root mean square fluctuation analysis (RMSF), and MM-GBSA analysis reveal that our newly identified phytochemicals form significant interactions in the binding pocket of 3CLPRO and form stable complexes, indicating that these phytochemicals could be used as potential antagonists for SARS-COV-2.

https://www.frontiersin.org/articles/10.3389/fmolb.2023.1060076/pdf

Identification of novel inhibitors for SARS-CoV-2 as therapeutic options using machine learning-based virtual screening, molecular docking and MD simulation

Introduction Monkeypox is a zoonotic disease caused by brick-shaped enveloped monkeypox (Mpox) virus that belongs to the family of ancient viruses known as Poxviridae. Subsequently, the viruses have been reported in various countries. The virus is transmitted by respiratory droplets, skin lesions, and infected body fluids. The infected patients experience fluid-filled blisters, maculopapular rash, myalgia, and fever. Due to the lack of effective drugs or vaccines, there is a need to identify the most potent and effective drugs to reduce the spread of monkeypox. The current study aimed to use computational methods to quickly identify potentially effective drugs against the Mpox virus. Methods In our study, the Mpox protein thymidylate kinase (A48R) was targeted because it is a unique drug target. We screened a library of 9000 FDA-approved compounds of the DrugBank database by using various in silico approaches, such as molecular docking and molecular dynamic (MD) simulation. Results Based on docking score and interaction analysis, compounds DB12380, DB13276, DB13276, DB11740, DB14675, DB11978, DB08526, DB06573, DB15796, DB08223, DB11736, DB16250, and DB16335 were predicted as the most potent. To examine the dynamic behavior and stability of the docked complexes, three compounds—DB16335, DB15796, and DB16250 —along with the Apo state were simulated for 300ns. The results revealed that compound DB16335 revealed the best docking score (-9.57 kcal/mol) against the Mpox protein thymidylate kinase. Discussion Additionally, during the 300 ns MD simulation period, thymidylate kinase DB16335 showed great stability. Further, in vitro and in vivo study is recommended for the final predicted compounds.

/pdf/computer-assisted-drug-repurposing-for-thymidylate-kinase-1nw00shy.pdf

Computer-assisted drug repurposing for thymidylate kinase drug target in monkeypox virus

Chalcone derivatives as xanthine oxidase inhibitors: synthesis, binding mode investigation, biological evaluation, and ADMET prediction.

Xanthine oxidase (XO) is a key target for gout treatment. Great efforts have been made towards the discovery and development of new XO inhibitors. Aureusidin (AUR), a natural compound, emerges as the second reported XO inhibitor with an aurone skeleton with an IC50 value of 7.617 ± 0.401 μM in vitro. The inhibitory mechanism of AUR against XO was explored through enzyme kinetic studies, multi-spectroscopic methods, computer simulation techniques, and ADME prediction. The results showed that AUR acts as a rapid reversible and mixed-type XO inhibitor and its binding to XO was driven by hydrogen bonding and hydrophobic interaction. Moreover, AUR presented a strong fluorescence quenching effect through a static quenching process and induced a conformation change of XO. Its binding pattern with XO was revealed through molecular docking, and its affinity toward XO was enhanced through interactions with key amino acid residues in the active pocket of XO. Further, AUR demonstrated good stability and pharmacokinetic behavior properties in molecular dynamics simulation and ADME prediction. In short, the current work clarified in depth the inhibitory mechanism of AUR on XO firstly and then provided fresh insights into its further development as a natural potent XO inhibitor with aurone skeleton.

/pdf/unveiling-the-inhibitory-mechanism-of-aureusidin-targeting-h2n85feo.pdf

Unveiling the inhibitory mechanism of aureusidin targeting xanthine oxidase by multi-spectroscopic methods and molecular simulations

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Identification of novel inhibitors for SARS-CoV-2 as therapeutic options using machine learning-based virtual screening, molecular docking and MD simulation

Computer-assisted drug repurposing for thymidylate kinase drug target in monkeypox virus

Chalcone derivatives as xanthine oxidase inhibitors: synthesis, binding mode investigation, biological evaluation, and ADMET prediction.

Unveiling the inhibitory mechanism of aureusidin targeting xanthine oxidase by multi-spectroscopic methods and molecular simulations