Synthesis, spectroscopic analysis, and computational-based investigations on 'azo-coumarin-Co(II)-galangin' hybrids exhibit multipotential activities.

The present study synthesized a series of cobalt (II) metal ion frame hybrid candidates (6a-6f) bearing phyto-flavonol galangin with substituted aryl diazenyl coumarins, and further structural confirmation was validated by various spectral techniques, including NMR, ATR-FTIR, UV-vis, HPLC, XRD, etc. Therapeutic potency was investigated via PASS (prediction of activity spectra for substances), molecular docking, molecular dynamics simulation, prediction of toxicity, pharmacokinetics, and drug-likeness scores, along with the highest occupied molecular orbital (HOMO), the lowest unoccupied molecular orbital (LUMO), with their energy gaps (ΔEH-L) to locate the most potential therapeutic candidates. The PASS prediction (Pa > Pi score) showed that proposed metal complexes have kinase inhibitors, antioxidative, and antischistosomal activities with potential molecular docking scores (> -7 kcal/mol) against selected targeted enzymes. Further, the MD-simulation (RMSD, RMSF, Rg, and H-bonds) of the most potential docking complex, 'HER2-6d', showed a minimum deviation similar to the standard drug (lapatinib) at 100 ns, indicating that 6d could be a potential noncovalent anticancer inhibitor. In addition, metal complexes possess a non-toxic and ideal drug-ability profiles, and positive electron space in an excited state increases the binding affinity towards target enzymes. Among all six ligands, 6c and 6d were the two most multipotent therapeutic agents from the above analyses. In summary, this could be a feasible approach towards the utilization of phytochemicals in mainstream therapeutic applications, where bioinformatics tools help to select a lead drug candidate at an early stage and guide for higher experimental success by proceeding with potential candidates.Communicated by Ramaswamy H. Sarma.

In Silico Identification of Potential Insect Peptides against Biofilm-Producing Staphylococcus aureus.

Biofilm-producing Staphylococcus aureus (SA) strains are frequently found in medical environments, from surgical/ wound sites, medical devices. These biofilms reduce the efficacy of applied antibiotics during the treatment of several infections, such as cystic fibrosis, endocarditis, or urinary tract infections. Thus, the development of potential therapeutic agents to destroy the extra protective biofilm layers or to inhibit the biofilm-producing enzymes is urgently needed. Advanced and cost-effective bioinformatics tools are advantageous in locating and speeding up the selection of antibiofilm candidates. Based on the potential drug characteristics, we have selected one-hundred thirty-three antibacterial peptides derived from insects to assess for their antibiofilm potency via molecular docking against five putative biofilm formation and regulated target enzymes: the staphylococcal accessory regulator A or SarA (PDB ID: 2FRH), 4,4'-diapophytoene synthase or CrtM (PDB ID: 2ZCQ), clumping factor A or ClfA (PDB ID: 1N67) and serine-aspartate repeat protein C or SdrC (PDB ID: 6LXH) and sortase A or SrtA (PDB ID: 1T2W) of SA bacterium. In this study, molecular docking was performed using HPEPDOCK and HDOCK servers, and molecular interactions were examined using BIOVIA Discovery Studio Visualizer-2019. The docking score (kcal/mol) range of five promising antibiofilm peptides against five targets was recorded as follows: diptericin A (-215.52 to -303.31), defensin (-201.11 to -301.92), imcroporin (-212.08 to -287.64), mucroporin (-228.72 to -286.76), apidaecin II (-203.90 to -280.20). Among these five, imcroporin and mucroporin were 13 % each, while defensin contained only 1 % of positive net charged residues (Arg+Lys) projected through ProtParam and NetWheels tools. Similarly, imcroporin, mucroporin and apidaecin II were 50 %, while defensin carried 21.05 % of hydrophobic residues predicted by the tool PEPTIDE. 2.0. Most of the peptides exhibited potential characteristics to inhibit S. aureus-biofilm formation via disrupting the cell membrane and cytoplasmic integrity. In summary, the proposed hypothesis can be considered a cost-effective platform for selecting the most promising bioactive drug candidates within a limited timeframe with a greater chance of success in experimental and clinical studies.

Experimental and clinical trial investigations of phyto-extracts, phyto-chemicals and phyto-formulations against oral lichen planus: A systematic review.

ETHNOPHARMACOLOGICAL RELEVANCE: Bio-assay guided phytoextracts and derived phytoconstituents reported having multipotent biological activities and nearly 60-80% of the global population still using natural regimens as an alternative therapeutic source. This study focused on the ethnopharmacological and experimental evidence of natural remedies that are effective in treating oral lichen planus (OLP), a chronic T-cell mediated autoimmune disease that is associated with oral cancer transmission. AIM OF THE REVIEW: A number of studies have shown that antioxidants and antiinflammatory phytoextracts and phyto-constituents are effective against OLP. In this systematic review, we summarize the details of experimentally assessed ancient Traditional Chinese Medicine (TCM), Indian Ayurveda or Ayurvedic Medicine, and Japanese Kampo Medicine (JKM) regimens (crude extracts, individual phytochemicals, and phyto-formulations) that reduce oral lesion, severity index and pain associated with OLP based on studies conducted in vivo, in vitro, and in randomized controlled trials (RCTs). MATERIALS AND METHODS: Experimental, clinical and RCT investigation reports were gathered and presented according to PRISMA-2020 format. Briefly, the information was obtained from PubMed, ScienceDirect, Wiley journal library, Scopus, Google Scholar with ClinicalTrials.gov (a clinical trial registry database operated by the National Library of Medicine in the United States). Further, individual phytochemical structures were verified from PubChem and ChemSpider databases and visualized by ChemDraw 18.0 software. RESULTS: We summarized 11 crude phytoextracts, 7 individual phytochemicals, 9 crude formulations, 8 specific TCM and JKM herbal cocktails, and 6 RCTs/patents corroborated by multiple in vitro, in vivo and enzyme assay methods. Briefly, plants and their family name, used plant parts, reported phytochemicals and their chemical structure, treatment doses, and duration of each experiment were presented more concisely and scientifically. CONCLUSION: Documentation of evidence-based natural ethnomedicines or remedies could be useful for promoting them as potential, cost-effective and less toxic alternatives or as complementary to commonly prescribed steroids towards the control of OLP.

Integrated bioinformatics-cheminformatics approach toward locating pseudo-potential antiviral marine alkaloids against SARS-CoV-2-Mpro.

The emergence of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) with the most contagious variants, alpha (B.1.1.7), beta (B.1.351), delta (B.1.617.2), and Omicron (B.1.1.529) has continuously added a higher number of morbidity and mortality, globally. The present integrated bioinformatics-cheminformatics approach was employed to locate potent antiviral marine alkaloids that could be used against SARS-CoV-2. Initially, 57 antiviral marine alkaloids and two repurposing drugs were selected from an extensive literature review. Then, the putative target enzyme SARS-CoV-2 main protease (SARS-CoV-2-Mpro) was retrieved from the protein data bank and carried out a virtual screening-cum-molecular docking study with all candidates using PyRx 0.8 and AutoDock 4.2 software. Further, the molecular dynamics (MD) simulation of the two most potential alkaloids and a drug docking complex at 100 ns (with two ligand topology files from PRODRG and ATB server, separately), the molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) free energy, and contributions of entropy were investigated. Then, the physicochemical-toxicity-pharmacokinetics-drug-likeness profiles, the frontier molecular orbitals energies (highest occupied molecular orbital, lowest unoccupied molecular orbital, and ΔE), and structural-activity relationship were assessed and analyzed. Based on binding energy, 8-hydroxymanzamine (-10.5 kcal/mol) and manzamine A (-10.1 kcal/mol) from all alkaloids with darunavir (-7.9 kcal/mol) and lopinavir (-7.4 kcal/mol) against SARS-CoV-2-Mpro were recorded. The MD simulation (RMSD, RMSF, Rg, H-bond, MM/PBSA binding energy) illustrated that the 8-hydroxymanzamine exhibits a static thermodynamic feature than the other two complexes. The predicted physicochemical, toxicity, pharmacokinetics, and drug-likeness profiles also revealed that the 8-hydroxymanzamine could be used as a potential lead candidate individually and/or synergistically with darunavir or lopinavir to combat SARS-CoV-2 infection after some pharmacological validation.

Combinatorial approach of vitamin C derivative and anti-HIV drug-darunavir against SARS-CoV-2.

BACKGROUND: Coronavirus disease-2019 (COVID-19) has become a pandemic around the globe due to the Severe Acute Respiratory Syndrome Corona Virus-2 (SARS-CoV-2), a new variant of the Coronavirus (CoV) family. The rapid transmission of the infectious disease, 135,646,617 positive cases from which 2,930,732 mortality cases were recorded until 11 April 2021. In an emergency, several existing anti-viral, anti-malarial, and anti-HIV drugs have been used on a repurposing basis. However, without proper clinical evidence, it may create several side effects for the patient. Thus, recommending potential and less-toxic regimens at this emergency stage is the most crucial aspect for any physician. METHODS: We have hypothesized a combinatorial drug approach against COVID-19 and to select potential combinations from ten anti-HIV drugs and ten vitamin C derivatives were systematically validated using advanced bioinformatic tools. Initially, the chemical structures used as ligands from PubChem and the target protein, SARS-CoV-2 main protease (PDB ID: 6Y84) from the protein data bank were retrieved for this study. Further, assess the potency, toxicity, drug-ability, and pharmacokinetics profiles using several bioinformatics tools, viz., molecular docking by the AutoDock 4.1 software with predicting activity spectra for substances, Molsoft, ProTox, and SwissADME tools. Molecular dynamics simulation was also employed for most potential candidates to assess their binding stability using GROMACS 5.1.4 software. RESULTS: The above computational investigation indicated that 'darunavir with L-ascorbyl-2,6-dibutyrate or ascorbic acid-2-sulfate' combinations strongly inhibit the SARS-CoV-2-main protease as a potential treatment option against COVID-19. Mostly, vitamin C derivatives enhanced the anti-COVID activity and might reduce the post-treatment side effects of darunavir in combination. CONCLUSIONS: Overall, the present work suggests that bioinformatics tools are suitable for recognizing potential candidates in an emergency, and herein the selected 'anti-HIV-drug-vitamin c derivatives' cocktails may potential-cum-fewer toxic regimens against COVID-19 treatment.

Antituberculosis, antioxidant and cytotoxicity profiles of quercetin: a systematic and cost-effective in silico and in vitro approach.

The ineffectiveness and the slowdown of newer anti-TB drug approval rates directly indicate searching for potential alternative agents. However, validation of isolated phytochemicals through hit-and-trial experiments is more expensive and time-consuming. Simultaneously, cost-effective computational tools can recognize most potential candidates at an initial stage. The present study selected seven plant-derived polyphenols, then verified anti-TB and drug-ability profiles using advanced computational tools before the experimental study. Among all, the quercetin showed a potential docking-score within -8 to -11 kcal/mol than the standard isoniazid and ofloxacin, -5 to -10 kcal/mol. Additionally, quercetin exhibited a higher drug-ability score of 0.53 than isoniazid 0.19. Further, quercetin exhibited the minimum inhibitory concentration at 6 and 8 µg/mL, while ofloxacin showed at 2 µg/mL against InhA, and katG mutated Mtb-strains, respectively. Parallelly, quercetin showed promising free-radical-scavenging activity from nitric-oxide assay at IC50 = 14.92 µg/mL, and lesser-cytotoxicity from cultured HepG2 cell lines at IC50 = 159 µg/mL, respectively.

Anti-HIV-drug and phyto-flavonoid combination against SARS-CoV-2: a molecular docking-simulation base assessment.

At the health emergence, no such potent prophylactic therapy is available to control the deadly emerged Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). However, existing antiviral, anti-inflammatory, antimalarial drugs is the only option against SARS-CoV-2, but it may be harmful to patients without more clinical evidence. As an alternative solution, we proposed a newer hypothesis using the selective 10 potent anti-HIV drugs and flavonoid class of phytochemicals from previous reports to use in combination against SARS-CoV-2. Primarily, 10 anti-HIV protease inhibitor drugs and 10 phyto-flavonoids as ligands in molecular docking study against the putative target, the SARS-CoV-2-main protease (Mpro) ID: 6Y2E), as an essential enzyme in viral genome replication. According to molecular docking and drug-ability scores of each ligand, the anti-HIV drug, the darunavir (with a docking score, -10.25 kcal/mol and drug-likeness rating, 0.60) and the quercetin-3-rhamnoside (with a docking score, -10.90 kcal/mol and drug-likeness rating, 0.82) were selected for further analysis in combined effect. Perceptibly, the combined 'anti-HIV drug and phyto-flavonoid' docking complex has actively interacted with eight strong H-bonds with stability, briefly elucidated through RMRD-, RMSF- Rg-plots and MM/PBSA-binding energy calculation during 100 ns than the individual against SARS-CoV-2-Mpro. Thus, the 'anti-HIV-drug-phyto-flavonoid' combination therapy could be used against SARS-CoV-2 after some experimental validation.Communicated by Ramaswamy H. Sarma.

Potential of Marine Terpenoids against SARS-CoV-2: An In Silico Drug Development Approach.

In an emergency, drug repurposing is the best alternative option against newly emerged severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. However, several bioactive natural products have shown potential against SARS-CoV-2 in recent studies. The present study selected sixty-eight broad-spectrum antiviral marine terpenoids and performed molecular docking against two novel SARS-CoV-2 enzymes (main protease or Mpro or 3CLpro) and RNA-dependent RNA polymerase (RdRp). In addition, the present study analysed the physiochemical-toxicity-pharmacokinetic profile, structural activity relationship, and phylogenetic tree with various computational tools to select the 'lead' candidate. The genomic diversity study with multiple sequence analyses and phylogenetic tree confirmed that the newly emerged SARS-CoV-2 strain was up to 96% structurally similar to existing CoV-strains. Furthermore, the anti-SARS-CoV-2 potency based on a protein-ligand docking score (kcal/mol) exposed that the marine terpenoid brevione F (-8.4) and stachyflin (-8.4) exhibited similar activity with the reference antiviral drugs lopinavir (-8.4) and darunavir (-7.5) against the target SARS-CoV-Mpro. Similarly, marine terpenoids such as xiamycin (-9.3), thyrsiferol (-9.2), liouvilloside B (-8.9), liouvilloside A (-8.8), and stachyflin (-8.7) exhibited comparatively higher docking scores than the referral drug remdesivir (-7.4), and favipiravir (-5.7) against the target SARS-CoV-2-RdRp. The above in silico investigations concluded that stachyflin is the most 'lead' candidate with the most potential against SARS-CoV-2. Previously, stachyflin also exhibited potential activity against HSV-1 and CoV-A59 within IC50, 0.16-0.82 µM. Therefore, some additional pharmacological studies are needed to develop 'stachyflin' as a drug against SARS-CoV-2.

Ultraflexible Liposome Nanocargo as a Dermal and Transdermal Drug Delivery System.

A selected active pharmaceutical ingredient must be incorporated into a cargo carrier in a particular manner so that it achieves its goal. An amalgamation of active pharmaceutical ingredients (APIs) should be conducted in such a manner that it is simple, professional, and more beneficial. Lipids/polymers that are known to be used in nanocarriers for APIs can be transformed into a vesicular formulation, which offers elegant solutions to many problems. Phospholipids with other ingredients, such as ethanol and water, form suitable vesicular carriers for many drugs, overcoming many problems related to poor bioavailability, poor solubility, etc. Ultraflexible liposomes are novel carriers and new frontiers of drug delivery for transdermal systems. Auxiliary advances in vesicular carrier research have been made, enabling polymer-coated ethanolic liposomes to avoid detection by the body's immune system-specifically, the cells of the reticuloendothelial system. Ultraflexible liposomes act as a cargo system and a nanotherapeutic approach for the transport of therapeutic drugs and bioactive agents. Various applications of liposome derivatives in different diseases are emphasized in this review.

Antimicrobial Peptides Derived From Insects Offer a Novel Therapeutic Option to Combat Biofilm: A Review.

Biofilms form a complex layer with defined structures, that attach on biotic or abiotic surfaces, are tough to eradicate and tend to cause some resistance against most antibiotics. Several studies confirmed that biofilm-producing bacteria exhibit higher resistance compared to the planktonic form of the same species. Antibiotic resistance factors are well understood in planktonic bacteria which is not so in case of biofilm producing forms. This may be due to the lack of available drugs with known resistance mechanisms for biofilms. Existing antibiotics cannot eradicate most biofilms, especially of ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species). Insects produce complex and diverse set of chemicals for survival and defense. Antimicrobial peptides (AMPs), produced by most insects, generally have a broad spectrum of activity and the potential to bypass the resistance mechanisms of classical antibiotics. Besides, AMPs may well act synergistically with classical antibiotics for a double-pronged attack on infections. Thus, AMPs could be promising alternatives to overcome medically important biofilms, decrease the possibility of acquired resistance and treatment of multidrug-resistant pathogens including ESKAPE. The present review focuses on insect-derived AMPs with special reference to anti-biofilm-based strategies. It covers the AMP composition, pathways and mechanisms of action, the formation of biofilms, impact of biofilms on human diseases, current strategies as well as therapeutic options to combat biofilm with antimicrobial peptides from insects. In addition, the review also illustrates the importance of bioinformatics tools and molecular docking studies to boost the importance of select bioactive peptides those can be developed as drugs, as well as suggestions for further basic and clinical research.