Fragment-Based Approaches Identified Tecovirimat-Competitive Novel Drug Candidate for Targeting the F13 Protein of the Monkeypox Virus.

Monkeypox is a serious public health issue in tropical and subtropical areas. Antivirals that target monkeypox proteins might lead to more effective and efficient therapy. The F13 protein is essential for the growth and maturation of the monkeypox virus. F13 inhibition might be a viable therapeutic target for monkeypox. The in silico fragment-based drug discovery method for developing antivirals may provide novel therapeutic options. In this study, we generated 800 compounds based on tecovirimat, an FDA-approved drug that is efficacious at nanomolar quantities against monkeypox. These compounds were evaluated to identify the most promising fragments based on binding affinity and pharmacological characteristics. The top hits from the chemical screening were docked into the active site of the F13 protein. Molecular dynamics simulations were performed on the top two probable new candidates from molecular docking. The ligand-enzyme interaction analysis revealed that the C2 ligand had lower binding free energy than the standard ligand tecovirimat. Water bridges, among other interactions, were shown to stabilize the C2 molecule. Conformational transitions and secondary structure changes in F13 protein upon C2 binding show more native three-dimensional folding of the protein. Prediction of pharmacological properties revealed that compound C2 may be promising as a drug candidate for monkeypox fever. However, additional in vitro and in vivo testing is required for validation.

Bis-1,3,4-Oxadiazole Derivatives as Novel and Potential Urease Inhibitors; Synthesis, In Vitro, and In Silico Studies.

AIMS: To synthesize bis-1,3,4-oxadiazole derivatives as novel and potential urease inhibitors. BACKGROUND: Despite many important biological activities associated with oxadiazoles, they are still neglected by medicinal chemists for their possible urease inhibitory activity. Keeping in view the countless importance of urease inhibitors, we have synthesized a new library of substituted bisoxadiazole derivatives (1-21) to evaluate their urease inhibitory potential. OBJECTIVE: The aim includes the synthesis of substituted bis-oxadiazole derivatives (1-21) in order to evaluate their urease inhibitory potential. METHODS: Bis-1,3,4-oxadiazole derivatives 1-21 were synthesized through sequential reactions using starting material isophthalic acid. Esterification reaction was done by refluxing in methanol for 2 h in the presence of the catalytic amount of concentrated H2SO4 till dissolution. In the second step, dimethyl isophthalate and hydrazine hydrate in excess (1:5) were refluxed in methanol to afford isophthalic dihydrazide. Then, isophthalic dihydrazide was treated with different substituted benzaldehydes in a 1:2 ratio under acidic conditions. RESULTS: In vitro urease, the inhibitory activity of the synthesized compounds was evaluated and the results demonstrated good activities with IC50 values in the range of 13.46 ± 0.34 to 74.45 ± 3.81 µM as compared to the standard thiourea (IC50 = 21.13 ± 0.415 µM). Most of the compounds were found to be more potent than the standard. The structure-activity relationship (SAR) suggested that the variations in the inhibitory activities of the compounds were due to different substitutions. Furthermore; in silico study was also performed. CONCLUSION: Current study identified a new class of urease inhibitors. All synthetic compounds 1-21 showed potent as well as good to moderate urease inhibitory activities except 3. SAR suggested that hydroxy-bearing analogs were identified exceptionally well. Molecular docking revealed many important interactions made by compounds with the active site of the urease enzyme.

In Silico Drug Designing for ala438 Deleted Ribosomal Protein S1 (RpsA) on the Basis of the Active Compound Zrl15.

Pyrazinoic acid-resistant tuberculosis is a severe chronic disorder. First-line drugs specifically target the ribosomal protein subunit-1 (RpsA) and stop trans-translation in the wild-type bacterium, causing bacterial cell death. In mutant bacterial strain, the deletion of ala438 does not let the pyrazinoic acid to bind to the active site of RpsA and ensures that the bacterium survives. Hence, such tuberculosis cases require an immediate and successful regime. The current study was designed to identify inhibitors that could bind to the mutant state of the RpsA protein. Initially, a pharmacophore model was generated based on the recently published most potent inhibitor for the mutant state of RpsA, i.e., zrl15. The validated pharmacophore model was further used for virtual screening of two chemical libraries, i.e., ZINC and ChemBridge. After applying the Lipinski rule of five (Ro5), a total of 260 and 749 hits from the ChemBridge and ZINC libraries, respectively, were identified using pharmacophore mapping. These hits were then docked into the active site of the mutant state of the RpsA protein, and later, the top 150 compounds from each library were chosen based on the docking score. A total of 21 compounds were shortlisted from each library based on the best protein-ligand interactions. Finally, a total of 05 compounds were subjected to molecular dynamics study to examine the dynamic behavior of each compound in the active site of the mutant state of the RpsA protein. The results revealed that all compounds had good chemical properties such as absorption, distribution, metabolism, excretion, and toxicity (ADMET), and there was no Pan Assay Interference (PAINS) or deviation from Ro5, indicating that these compounds could be useful antagonists for the mutant state of the RpsA protein.

Identification of a Potential Vaccine against Treponema pallidum Using Subtractive Proteomics and Reverse-Vaccinology Approaches.

Syphilis, a sexually transmitted infection, is a deadly disease caused by Treponema pallidum. It is a Gram-negative spirochete that can infect nearly every organ of the human body. It can be transmitted both sexually and perinatally. Since syphilis is the second most fatal sexually transmitted disease after AIDS, an efficient vaccine candidate is needed to establish long-term protection against infections by T. pallidum. This study used reverse-vaccinology-based immunoinformatic pathway subtractive proteomics to find the best antigenic proteins for multi-epitope vaccine production. Six essential virulent and antigenic proteins were identified, including the membrane lipoprotein TpN32 (UniProt ID: O07950), DNA translocase FtsK (UniProt ID: O83964), Protein Soj homolog (UniProt ID: O83296), site-determining protein (UniProt ID: F7IVD2), ABC transporter, ATP-binding protein (UniProt ID: O83930), and Sugar ABC superfamily ATP-binding cassette transporter, ABC protein (UniProt ID: O83782). We found that the multiepitope subunit vaccine consisting of 4 CTL, 4 HTL, and 11 B-cell epitopes mixed with the adjuvant TLR-2 agonist ESAT6 has potent antigenic characteristics and does not induce an allergic response. Before being docked at Toll-like receptors 2 and 4, the developed vaccine was modeled, improved, and validated. Docking studies revealed significant binding interactions, whereas molecular dynamics simulations demonstrated its stability. Furthermore, the immune system simulation indicated significant and long-lasting immunological responses. The vaccine was then reverse-transcribed into a DNA sequence and cloned into the pET28a (+) vector to validate translational activity as well as the microbial production process. The vaccine developed in this study requires further scientific consensus before it can be used against T. pallidum to confirm its safety and efficacy.

Review on Pharmacological and Phytochemical Prospects of Traditional Medicinal Plant: Persicaria hydropiper (Smartweed).

Persicaria hydropiper (L.) Delarbre (family Polygonacea), commonly known as Polygonum hydropiper, is a popular medicinal plant used in traditional medicine. The plant is indigenous to the tropical northern hemisphere and temperate zone, including China, Bangladesh, India, and Japan. The plant is used in folk medicine for numerous ailments such as hemorrhoids, antifertility, diarrhea, and dyspepsia. Its medicinal usage in Unani, Ayurveda, Siddha, and other traditional medicine is well-recognized. So far, a wide range of active phytochemicals of this plant has been identified, such as flavonoids, sulphated flavonoids, terpenoids, anthraquinones, steroids, coumarin, simple phenolics, and others. Pharmacological data reported in the literature suggest that various parts of P. hydropiper exhibit antimicrobial, antioxidant, hypoglycemic, antidepressant, cardioprotective, hepatoprotective, anticancer, and antifertility effects. The present review aims to compile the coherently document research on the phytochemical, pharmacological, and biological activities of P. hydropiper from different parts of the globe.

Improved color stability of anthocyanins in the presence of ascorbic acid with the combination of rosmarinic acid and xanthan gum.

This study investigated the protective effect and mechanism of action of combined use of rosmarinic acid (RA) and xanthan gum (XG) on the stability of anthocyanins (ACNs) in the presence of l-ascorbic acid (pH 3.0). The addition of RA and XG, alone and in combination, significantly enhanced the color stability of ACNs, and the combined use of RA and XG showed the best effect. FTIR, 1H NMR, AFM and computational molecular simulation analyses revealed that the improvement in ACN stability following the combined addition of RA and XG was due to intermolecular interactions such as hydrogen bonding and van der Waals forces. In the ACN-RA-XG ternary complexes, XG had stronger binding interactions with ACNs than RA. Our findings provide a valuable potential to enhance the stability of ACNs in the presence of ascorbic acid with the combined use of RA and XG.

Structural insights into the Zika virus NS1 protein inhibition using a computational approach.

Zika virus is part of the flaviviruses that spread through the Aedes mosquito species and causes neurological infectious diseases. The non-structural protein 1 (NS1) is an essential enzyme that is involved in the replication of Zika virus. In this study, the newly isolated flavonoid analogs were docked against the NS1 protein. Most of the compounds showed strong interactions with favorable binding energies in the active site of NS1. One of the suitable docked ligand-protein complexes was simulated along with the apo form of the enzyme for 100 ns. The simulation results validated the docking data. The molecular dynamics simulation analysis comprising of root mean square deviation and fluctuation, the radius of gyration, hydrogen bonding, potential energy, principle component analysis, and MM/PBSA revealed about the stability of the apo and complex systems. These flavonoids analogs can inhibit the hexamerization of the NS1 which is necessary for the Zika virus replication.Communicated by Ramaswamy H. Sarma.

Synthesis and screening of (E)-3-(2-benzylidenehydrazinyl)-5,6-diphenyl-1,2,4-triazine analogs as novel dual inhibitors of α-amylase and α-glucosidase.

(E)-3-(2-Benzylidenehydrazinyl)-5,6-diphenyl-1,2,4-triazines analogs 1-27 were synthesized by multi-step reaction scheme and subjected to in vitro inhibitory screening against α-amylase and α-glucosidase enzymes. Out of these twenty-seven synthetic analogs, ten compounds 14-17, 19, and 21-25 are structurally new. All compounds exhibited good to moderate inhibitory potential in terms of IC50 values ranging (IC50 = 13.02 ± 0.04-46.90 ± 0.05 µM) and (IC50 = 13.09 ± 0.08-46.44 ± 0.24 µM) in comparison to standard acarbose (IC50 = 12.94 ± 0.27 µM and 10.95 ± 0.08 µM), for α-amylase and α-glucosidase, respectively. Structure-activity relationship indicated that analogs with halogen substitution(s) were found more active as compared to compounds bearing other substituents. Kinetic studies on most active α-amylase and α-glucosidase inhibitors 5, 7, 9, 15, 24, and 27, suggested non-competitive and competitive types of inhibition mechanism for α-amylase and α-glucosidase, respectively. Molecular docking studies predicted the good protein-ligand interaction (PLI) profile with key interactions such as arene-arene, H-<, <-<, and <-H etc., against the corresponding targets.

Syntheses, in vitro α-amylase and α-glucosidase dual inhibitory activities of 4-amino-1,2,4-triazole derivatives their molecular docking and kinetic studies.

Thirty-three 4-amino-1,2,4-triazole derivatives 1-33 were synthesized by reacting 4-amino-1,2,4-triazole with a variety of benzaldehydes. The synthetic molecules were characterized via1H NMR and EI-MS spectroscopic techniques and evaluated for their anti-hyperglycemic potential. Compounds 1-33 exhibited good to moderate in vitro α-amylase and α-glucosidase inhibitory activities in the range of IC50 values 2.01 ± 0.03-6.44 ± 0.16 and 2.09 ± 0.08-6.54 ± 0.10 µM as compared to the standard acarbose (IC50 = 1.92 ± 0.17 µM) and (IC50 = 1.99 ± 0.07 µM), respectively. The limited structure-activity relationship suggested that different substitutions on aryl part of the synthetic compounds are responsible for variable activity. Kinetic study predicted that compounds 1-33 followed mixed and non-competitive type of inhibitions against α-amylase and α-glucosidase enzymes, respectively. In silico studies revealed that both triazole and aryl ring along with different substitutions were playing an important role in the binding interactions of inhibitors within the enzyme pocket. The synthetic molecules were found to have dual inhibitory potential against both enzymes thus they may serve as lead candidates for the drug development and research in the future studies.

Antihyperuricemic effect of dietary polyphenol sinapic acid commonly present in various edible food plants.

The present study was conducted to evaluate the antihyperuricemic effect of sinapic acid (SA). The results showed that SA potently inhibited xanthine oxidase (XOD) in a dose-dependent manner by entering the enzyme active site and thwarting the entrance of the substrate. These results were further confirmed by the quantum chemical descriptors analysis and 1 H NMR titration analysis. The in vivo results indicated that SA not only has the potential to inhibit serum and hepatic XOD (p < .05), but also remarkably lowered serum and urine uric acid levels at 50 and 100 mg/kg bw. Furthermore, SA regulated serum creatinine and blood urea nitrogen levels to normal and lowered inflammation in the renal tubules. Thus, the utilization of SA as an antihyperuricemic agent may have considerable potential for the development of functional foods for the possible treatment of hyperuricemia. PRACTICAL APPLICATIONS: Plant-derived bioactive compounds have multiple health benefits. The present study assesses the effects of sinapic acid against hyperuricemia. The results suggested that sinapic acid may have a strong protective effect against uric acid-related complications and may be used for the formulation of functional foods. However, further mechanistic studies are required to verify this hypothesis.

Molecular docking and simulation of Zika virus NS3 helicase.

The Zika virus (ZIKV) has gained attention for the last few years due to the congenital microcephaly and Guillain-Barre Syndrome that resulted in humans. The non-structural protein-3 (NS3) helicase of ZIKV play an important role in viral RNA replication. In this article, we performed hundred nanosecond molecular dynamics simulation and molecular docking of the NS3 helicase of ZIKV with 1,4-benzothiazine derivatives. The root mean square deviation (RMSD) analyses showed the stability of the NS3 helicase. The simulation showed that the flexible and rigid domains of the protein play a crucial role during the RNA replication process. All such domains with ligand binding pockets can be targeted for drug design. The molecular docking showed that the strong hydrogen bonding and arene-cation interactions are responsible for the binding between NS3 and 1,4-benzothiazine derivatives, which provides a new dimension for potent drug design for ZIKV.

Synthesis of quinoline derivatives as diabetic II inhibitors and molecular docking studies.

In searchof the potenttherapeutic agent as an α-glucosidase inhibitor, we have synthesized twenty-five analogs (1-25) of quinoline-based Schiff bases as an inhibitoragainst α-glucosidase enzyme under positive control acarbose (IC50 = 38.45 ±â€¯0.80 µM). From the activity profile it was foundthat analogs 1, 2, 3, 4, 11, 12 and 20with IC50values 12.40 ±â€¯0.40, 9.40 ±â€¯0.30, 14.10 ±â€¯0.40, 6.20 ±â€¯0.30, 14.40 ±â€¯0.40, 7.40 ±â€¯0.20 and 13.20 ±â€¯0.40 µMrespectively showed most potent inhibition among the series even than standard drug acarbose (IC50 = 38.45 ±â€¯0.80 µM). Here in the present study analog 4 (IC50 = 6.20 ±â€¯0.30 µM) was found with many folds better α-glucosidase inhibitory activity than the reference drug. Eight analogs like 5, 7, 8, 16, 17, 22, 24 and 25 among the whole series displayed less than 50% inhibition. The substituents effects on phenyl ring thereby superficially established through SAR study. Binding interactions of analogs and the active site of ligands proteins were confirmed through molecular docking study. Spectroscopic techniques like 1H NMR, 13C NMR and ESIMS were used for characterization.

A facile isoelectric focusing of myoglobin and hemoglobin used as markers for screening of chicken meat quality in China.

A novel analytical protocol was developed for general quality screening of chicken meat based on IEF and protein extraction. To demonstrate the developed protocol, 24 chickens were divided into three groups; each had eight chickens. The chickens in Group 1 were slaughtered by exsanguination, Group 2 asphyxiated in water, and that in Group 3 were infected by new castle disease virus. Proteins were extracted from the meat samples by using pure water as an extractant, separated by IEF, verified by western blot, and quantified via imaging analysis. The relevant experiments demonstrated that two myoglobin (Mb) bands were detected at pI 6.8 and 7.04 for all samples of Groups 1, 2, and 3, but there were additional hemoglobin (Hb) bands at pI 7.09 and 7.13 (P < 0.05) for the samples of Groups 2 and 3. The results implied that Hb bands might be a potential biomarker for the screening of chicken meat quality. The RSD values of two Mb bands (pI 6.8 and 7.04) in Group 1 were respectively 4.08 and 3.63%, the ones of two Hb bands (pI 7.09 and 7.13) in Group 2 were 3.66 and 2.10%, and those in Group 3 were 2.17% and 2.77%, respectively. All the RSD values indicated high stability and reliability of the developed protocol. Additionally, the protocol had a direct readout of protein bands in IEF without staining. However, it was time-consuming and had high cost. Even so, the relevant general method and finding have potential for screening of chicken meat quality.

Isatin based Schiff bases as inhibitors of α-glucosidase: Synthesis, characterization, in vitro evaluation and molecular docking studies.

Isatin base Schiff bases (1-20) were synthesized, characterized by (1)H NMR and EI/MS and evaluated for α-glucosidase inhibitory potential. Out of these twenty (20) compounds only six analogs showed potent α-glucosidase inhibitory potential with IC50 value ranging in between 2.2±0.25 and 83.5±1.0µM when compared with the standard acarbose (IC50=840±1.73µM). Among the series compound 2 having IC50 value (18.3±0.56µM), 9 (83.5±1.0µM), 11 (3.3±0.25µM), 12 (2.2±0.25µM), 14 (11.8±0.15µM), and 20 (3.0±0.15µM) showed excellent inhibitory potential many fold better than the standard acarbose. The binding interactions of these active analogs were confirmed through molecular docking.

Triazinoindole analogs as potent inhibitors of α-glucosidase: synthesis, biological evaluation and molecular docking studies.

A new series of triazinoindole analogs 1-11 were synthesized, characterized by EI-MS and (1)H NMR, evaluated for α-glucosidase inhibitory potential. All eleven (11) analogs showed different range of α-glucosidase inhibitory potential with IC50 value ranging between 2.46±0.008 and 312.79±0.06 µM when compared with the standard acarbose (IC50, 38.25±0.12 µM). Among the series, compounds 1, 3, 4, 5, 7, 8, and 11 showed excellent inhibitory potential with IC50 values 2.46±0.008, 37.78±0.05, 28.91±0.0, 38.12±0.04, 37.43±0.03, 36.89±0.06 and 37.11±0.05 µM respectively. All other compounds also showed good enzyme inhibition. The binding modes of these analogs were confirmed through molecular docking.