In Silico Screening of Potential Phytocompounds from Several Herbs against SARS-CoV-2 Indian Delta Variant B.1.617.2 to Inhibit the Spike Glycoprotein Trimer

In October 2020, the SARS-CoV-2 B.1.617 lineage was discovered in India. It has since become a prominent variant in several Indian regions and 156 countries, including the United States of America. The lineage B.1.617.2 is termed the delta variant, harboring diverse spike mutations in the N-terminal domain (NTD) and the receptor-binding domain (RBD), which may heighten its immune evasion potentiality and cause it to be more transmissible than other variants. As a result, it has sparked substantial scientific investigation into the development of effective vaccinations and anti-viral drugs. Several efforts have been made to examine ancient medicinal herbs known for their health benefits and immune-boosting action against SARS-CoV-2, including repurposing existing FDA-approved anti-viral drugs. No efficient anti-viral drugs are available against the SARS-CoV-2 Indian delta variant B.1.617.2. In this study, efforts were made to shed light on the potential of 603 phytocompounds from 22 plant species to inhibit the Indian delta variant B.1.617.2. We also compared these compounds with the standard drug ceftriaxone, which was already suggested as a beneficial drug in COVID-19 treatment; these compounds were compared with other FDA-approved drugs: remdesivir, chloroquine, hydroxy-chloroquine, lopinavir, and ritonavir. From the analysis, the identified phytocompounds acteoside (−7.3 kcal/mol) and verbascoside (−7.1 kcal/mol), from the plants Clerodendrum serratum and Houttuynia cordata, evidenced a strong inhibitory effect against the mutated NTD (MT-NTD). In addition, the phytocompounds kanzonol V (−6.8 kcal/mol), progeldanamycin (−6.4 kcal/mol), and rhodoxanthin (−7.5 kcal/mol), from the plant Houttuynia cordata, manifested significant prohibition against RBD. Nevertheless, the standard drug, ceftriaxone, signals less inhibitory effect against MT-NTD and RBD with binding affinities of −6.3 kcal/mol and −6.5 kcal/mol, respectively. In this study, we also emphasized the pharmacological properties of the plants, which contain the screened phytocompounds. Our research could be used as a lead for future drug design to develop anti-viral drugs, as well as for preening the Siddha formulation to control the Indian delta variant B.1.617.2 and other future SARS-CoV-2 variants.

Processing and Compatibility of Corydalis yanhusuo: Phytochemistry, Pharmacology, Pharmacokinetics, and Safety

Processed and polyherbal formulations (compatibility) are widely used in traditional Chinese medicine (TCM). However, processing and compatibility may alter the efficacy and safety of herbal medicines, and therefore, evaluating the herbal medicines changes after processing and compatibility is important for their safety. Since Corydalis yanhusuo (Y.H.Chou & Chun C.Hsu) W.T.Wang ex Z.Y.Su & C.Y.Wu (Family: Papaveraceae and Genera: Corydalis), a traditional medicinal plant in China, Japan, Korea, and other Asian countries, has been used for treating a wide range of medical conditions, it is an ideal representative of studying the effects of processing and compatibility on efficacy and toxicity. In this paper, information was obtained by searching electronic databases, classic books, PhD and MSc dissertations, local conference papers, and unpublished materials prior to July 2021. We provide a summary of the phytochemistry, pharmacology, pharmacokinetics, quality control, and safety of C. yanhusuo under various processing or compatibility conditions. Based on our findings, vinegar processing is probably the best C. yanhusuo processing method, which could increase the absorption rate of tetrahydropalmatine (THP) in the heart, liver, spleen, lung, and brain tissues and alleviate mice muscle tremors and liver damage caused by C. yanhusuo. These results indicate that processing and compatibility can reduce toxicity and increase the efficacy of C. yanhusuo. The information provides an expanded understanding of the efficacy and toxicity mechanisms of TCM compounds, which is valuable for industrial production quality control and future drug research.

Antioxidant, Analgesic and CNS Depressant Activities of Commelina diffusa Burm. f.

Commelina diffusa Burm. f. is a member of Commelinaceae family, which is widely grown in crop land and treated as a weed. This plant has several important medicinal properties which have not been studied extensively. In this study, the crude powder of C. diffusa whole plant was extracted with 95% ethanol and different solvent fractions (n-hexane, chloroform and methanol) were prepared from the crude extract by solvent-solvent partitioning. All these plant samples were subjected to bioassays for evaluating the antioxidant, central analgesic, peripheral analgesic and CNS depressant activities. The crude extract and its methanol soluble fraction showed mild free DPPH scavenging property with IC50 values of 98.49- and 84.77-μg/ml, respectively as compared to the standard ascorbic acid (IC50 = 2.67 μg/ml). In the analgesic activity test, the n-hexane fraction of C. diffusa at doses of 200- and 400-mg/kg body weight exhibited significant (p<0.05) central analgesic activity (tail flick test) in mice. Similarly, all the test samples showed statistically significant (p<0.05) reduction in abdominal writhing induced by acetic acid. C. diffusa showed significant CNS depressant activity which was measured by ‘open field test’ and ‘hole cross test’. Considering the potential bioactivities, the plant materials can be further studied elaborately to explore the activities of the purified compounds to aid in future drug development. Dhaka Univ. J. Pharm. Sci. 20(2): 159-166, 2021 (December)

The antidepressants effects on microbiota: unobvious possibilities Research article

Despite the emergence of new antidepressants with different mechanisms of action, a large number of problems in antidepressant therapy remain. Considering the known antimicrobial activity of antidepressants, the role of the microbiota in the thymoanaleptic activity of these drugs is of high interest. In recent years, important data have been obtained on the role of the gut microbiota in the regulation of behavior and the pathophysiology of a number of mental disorders, including depression. Of particular interest is the assessment of the normal intestinal microbiota role in the course of the therapeutic process. The emerging bi-directional interactions between drugs and microorganisms may be critical for personalized drug selection and future drug development. However, at the present time, this problem remains poorly understood. The proposed manuscript articulates the main directions that are of clinical importance and can become an object for further study in this area.The research results indicate that the effect of antidepressants on the microbiota is a promising area, the study of which could provide many important findings for clinical practice. This type of therapeutic manipulation can provide an opportunity for intervention in order to potentiate the activity of antidepressants or to minimize side effects. The problem with this method of intervention is enormous complexity, when manipulations can have both positive and negative effects simultaneously, depending on different strains of microorganisms influencing different therapeutic effects. More research is needed to understand what changes occur in the microbiome with acute and chronic administration of specific antidepressants. Perhaps this will contribute to the development of microbiomodulatory tactics for individualized interventions.

Mannich Bases: Centrality in Cytotoxic Drug Design

: Mannich bases identified by Professor Carl Mannich have been the most extensively explored scaffolds for more than 100 years now. The versatile biological roles that they play have promoted their applications in many clinical conditions. The present review highlights the application of Mannich bases as cytotoxic agents, categorizing them into synthetic, semisynthetic and prodrugs classes and gives an exhaustive account of the work reported in the last two decades. The methods of synthesis of these cytotoxic agents, their anti-cancer potential in various cell lines and promising leads for future drug development have also been discussed. Structure-activity relationships along with the targets on which these cytotoxic Mannich bases act have been included as well.

Potential Therapeutic Targets for Combination Antibody Therapy against Pseudomonas aeruginosa Infections

Despite advances in antimicrobial therapy and even the advent of some effective vaccines, Pseudomonas aeruginosa (P. aeruginosa) remains a significant cause of infectious disease, primarily due to antibiotic resistance. Although P. aeruginosa is commonly treatable with readily available therapeutics, these therapies are not always efficacious, particularly for certain classes of patients (e.g., cystic fibrosis (CF)) and for drug-resistant strains. Multi-drug resistant P. aeruginosa infections are listed on both the CDC’s and WHO’s list of serious worldwide threats. This increasing emergence of drug resistance and prevalence of P. aeruginosa highlights the need to identify new therapeutic strategies. Combinations of monoclonal antibodies against different targets and epitopes have demonstrated synergistic efficacy with each other as well as in combination with antimicrobial agents typically used to treat these infections. Such a strategy has reduced the ability of infectious agents to develop resistance. This manuscript details the development of potential therapeutic targets for polyclonal antibody therapies to combat the emergence of multidrug-resistant P. aeruginosa infections. In particular, potential drug targets for combinational immunotherapy against P. aeruginosa are identified to combat current and future drug resistance.

Improving Small-Molecule Force Field Parameters in Ligand Binding Studies

Small molecules are major players of many chemical processes in diverse fields, from material science to biology. They are made by a combination of carbon and heteroatoms typically organized in system-specific structures of different complexity. This peculiarity hampers the application of standard force field parameters and their in silico study by means of atomistic simulations. Here, we combine quantum-mechanics and atomistic free-energy calculations to achieve an improved parametrization of the ligand torsion angles with respect to the state-of-the-art force fields in the paradigmatic molecular binding system benzamidine/trypsin. Funnel-Metadynamics calculations with the new parameters greatly reproduced the high-resolution crystallographic ligand binding mode and allowed a more accurate description of the binding mechanism, when the ligand might assume specific conformations to cross energy barriers. Our study impacts on future drug design investigations considering that the vast majority of marketed drugs are small-molecules.

Epstein–Barr Virus Epithelial Cancers—A Comprehensive Understanding to Drive Novel Therapies

Epstein–Barr virus (EBV) is a ubiquitous oncovirus associated with specific epithelial and lymphoid cancers. Among the epithelial cancers, nasopharyngeal carcinoma (NPC), lymphoepithelioma-like carcinoma (LELC), and EBV-associated gastric cancers (EBVaGC) are the most common. The role of EBV in the pathogenesis of NPC and in the modulation of its tumour immune microenvironment (TIME) has been increasingly well described. Much less is known about the pathogenesis and tumour–microenvironment interactions in other EBV-associated epithelial cancers. Despite the expression of EBV-related viral oncoproteins and a generally immune-inflamed cancer subtype, EBV-associated epithelial cancers have limited systemic therapeutic options beyond conventional chemotherapy. Immune checkpoint inhibitors are effective only in a minority of these patients and even less efficacious with molecular targeting drugs. Here, we examine the key similarities and differences of NPC, LELC, and EBVaGC and comprehensively describe the clinical, pathological, and molecular characteristics of these cancers. A deeper comparative understanding of these EBV-driven cancers can potentially uncover targets in the tumour, TIME, and stroma, which may guide future drug development and cast light on resistance to immunotherapy.

The Zoonotic Helminth Parasite Fasciola hepatica: Virulence-Associated Cathepsin B and Cathepsin L Cysteine Peptidases Secreted by Infective Newly Excysted Juveniles (NEJ)

Fasciolosis caused by Fasciola hepatica is a major global disease of livestock and an important neglected helminthiasis of humans. Infection arises when encysted metacercariae are ingested by the mammalian host. Within the intestine, the parasite excysts as a newly excysted juvenile (NEJ) that penetrates the intestinal wall and migrates to the liver. NEJ excystment and tissue penetration are facilitated by the secretion of cysteine peptidases, namely, cathepsin B1 (FhCB1), cathepsin B2 (FhCB2), cathepsin B3 (FhCB3) and cathepsin L3 (FhCL3). While our knowledge of these peptidases is growing, we have yet to understand why multiple enzymes are required for parasite invasion. Here, we produced functional recombinant forms of these four peptidases and compared their physio-biochemical characteristics. Our studies show great variation of their pH optima for activity, substrate specificity and inhibitory profile. Carboxy-dipeptidase activity was exhibited exclusively by FhCB1. Our studies suggest that, combined, these peptidases create a powerful hydrolytic cocktail capable of digesting the various host tissues, cells and macromolecules. Although we found several inhibitors of these enzymes, they did not show potent inhibition of metacercarial excystment or NEJ viability in vitro. However, this does not exclude these peptidases as targets for future drug or vaccine development.