Biochemical Characterization of Different Chemical Components of Parthenium hysterophorus and Their Therapeutic Potential against HIV-1 RT and Microbial Growth.

Parthenium hysterophorus possesses certain allelochemicals responsible for their medicinal effects. The presence of oils, polyphenols, alkaloids, terpenes, pseudoguaianolides, and histamines in P. hysterophorus has been shown to exhibit medicinal properties. However, the systematic biomedical properties of this plant are still unexplored. The extracts of leaves, stem, and flower of P. hysterophorus, both at low and high temperatures (equivalent to boiling points of different solvents) were prepared. The extracts prepared in hexane, ethylacetate, methanol, and water were analyzed spectrophotometrically and colorimetrically and resolved on TLC for the presence of phytochemicals. The analyses of the free radical quenching potential of plant extracts were done by DPPH assay. The total antioxidant capacity was determined by phosphomolybdate assay and the ferric reducing antioxidant power (FRAP) assay was used to determine the reduction potential of the extracts. The spectrophotometric and qualitative analysis of plant extracts demonstrated the presence of alkaloids, terpenoids, carbohydrates, and cardiac glycosides. The occurrence of more than one Rf values for extracts determined by TLC indicated the presence of more than one phytochemical compound. The P. hysterophorus extracts contained strong antioxidant activity. These extracts exhibited strong antimicrobial activity against Staphylococcus epidermis, Salmonela typhi, Neisseria gonococci or gonococci, Citrobacter, and Shigella flexineri. The evaluation of the antimicrobial potential of P. hysterophorus extracts was done by the disc diffusion method. These extracts also showed significant inhibition against HIV-1 RT activity. The anti-HIV-1 RT activity was done using Roche Kit. The P. hysterophorus extracts displayed the presence of many phytochemicals with strong antioxidant, antimicrobial, and anti-HIV-1 RT properties.

Pharmacological Chemistry and Biomedical Implications of Chemical Ingredients from Parthenium hysterophorus.

Parthenium hysterophorus L. belonging to the family Asteraceae is a noxious weed infestation with allelopathic effects with its lower economic value. It poses a serious risk to its surroundings. The presence of oils, polyphenols, flavones, flavonoids, alkaloids, terpenes, pseudoguaianolides, and histamines in P. hysterophorus makes it important and beneficial due to its medicinal properties. This review article is focused on the history, geographical distribution, chemical composition, and molecular structure of some phytochemicals and ethanopharmacological aspects of P. hysterophorus. The harmful effects of this weed have also been included. The information available from the existing literature revealed that P. hysterophorus is rich in various phytochemicals with different pharmacological activities. However, the complete analysis of different phytoconstituents isolated from P. hysterophorus and their specific properties are not fully understood. The sporadic information published in some journals suggests that this plant could be exploited to develop new drugs against certain diseases, including cancer, HIV-1 infection, and immunological disorders. The structure and mode of action of some compounds such as parthenin and stigmasterol were also discussed. Though the current information on P. hysterophorus indicates the ethnopharmacological implications of extracts of this plant, more systematic and extensive studies are still required to properly understand the contribution of its specific chemical constituents responsible for their various medicinal properties.

In silico study indicates antimalarials as direct inhibitors of SARS-CoV-2-RNA dependent RNA polymerase.

Coronavirus disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has caused a global pandemic. RNA-dependent RNA polymerase (RdRp) is the key component of the replication or transcription machinery of coronavirus. Therefore SARS-CoV-2-RdRp has been chosen as an important target for the development of antiviral drug(s). During the early pandemic of the COVID-19, chloroquine and hydroxychloroquine were suggested by the researchers for the prevention or treatment of SARS-CoV-2. In our study, the antimalarial compounds have been screened and docked against SARS-CoV-2-RdRp (PDB ID: 7BTF), and it was observed that the antimalarials chloroquine, hydroxychloroquine, and amodiaquine exhibit good affinity. Since the crystal structure of SARS-CoV-2-RdRp with its substrate is not available, poliovirus-RdRp crystal structure co-crystallized with its substrate ATP (PDB ID: 2ILY) was used as a reference structure. The superimposition of SARS-CoV-2-RdRp and poliovirus-RdRp structures showed that the active sites of both of the RdRps superimposed very well. The amino acid residues involved in the binding of ATP in the case of poliovirus-RdRp and residues involved in binding with the antimalarial compounds with SARS-CoV-2-RdRp were compared. In both cases, the conserved residues were found to be involved in establishing the interactions. The MMGBSA and molecular dynamic simulation studies were performed to strengthen our docking results. Further residues involved in binding of antimalarials with SARS-CoV-2-RdRp were compared with the residues involved in the SARS-CoV-2-RdRp complexed with remdesivir [PDB ID: 7BV2]. It was observed that co-crystallized remdesivir and docked antimalarials bind in the same pocket of SARS-CoV-2 -RdRp.Communicated by Ramaswamy H. Sarma.

Repurposing of gastric cancer drugs against COVID-19.

Corona Virus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has become a global pandemic. Additionally, the SARS-CoV-2 infection in the patients of Gastric Cancer (GC; the third leading cause of death in the world) pose a great challenge for the health management of the patients. Since there have been uncertainties to develop a new drug against COVID-19, there is an urgent need for repurposing drugs that can target key proteins of both SARS-CoV-2 and GC. The SARS-CoV-2-RdRp protein contains the NiRAN domain, which is known to have kinase-like folds. A docking study of the FDA approved drugs against GC was performed using AutoDock 4.2 and Glide Schrodinger suite 2019 against SARS-CoV-2-RdRp protein. MMGBSA and MD simulation studies were performed to investigate the binding and stability of the inhibitors with the target protein. In this study, we have found 12 kinase inhibitors with high binding energies namely Baricitinib, Brepocitinib, Decernotinib, Fasudil, Filgotinib, GSK2606414, Peficitinib, Ruxolitinib, Tofacitinib, Upadacitinib, Pamapimod and Ibrutinib. These FDA approved drugs against GC can play a key role in the treatment of COVID-19 patients along with GC as comorbidity. We also hypothesize that JAK, ITK, Rho-associated kinases, FGFR2, FYN, PERK, TYK2, p38-MAPK and SYK kinases can be considered as key therapeutic targets in COVID-19 treatment. Taken altogether, we have proposed the SARS-CoV-2-RdRp as a potential therapeutic target through in-silico studies. However, further in-vitro and in-vivo studies are required for the validation of the proposed targets and drugs for the treatment of COVID-19 patients already suffering from GC.

Modulating catalytic activity of human topoisomerase II α enzyme by fluorescent gold nanoclusters.

Precise monitoring of the enzyme activity by a suitable modulator is one of the very fundamental aspects of drug designing that provides the opportunity to overcome the challenges of several diseases. Herein, inhibition of human Topoisomerase IIα enzyme which serves as a potential target site for several anti-cancer drugs is demonstrated by using ultra-small size gold nanoclusters (Au NCs) with the dimension comparable with size of the active site of the enzyme. Molecular dynamics simulation results demonstrate that the Au NCs strongly interact with the human Topo IIα enzyme at its active site or allosteric site depending on forms of enzyme. Additionally, binding energy and interaction profile provides the molecular basis of understanding of interactions of ultra-small size Au NCs and human Topo IIα enzyme. Enthalpy change (ΔH) and binding constant (K) are measured based on a sequential binding model of the Au NCs with the enzyme as demonstrated by the ITC study. Moreover, the in-vitro inhibition study of the catalytic activity of the enzyme and gel electrophoresis indicates that the ultra-small size Au NCs may be used as a potent inhibitor of human Topo IIα enzyme.

Single tryptophan of disordered loop from Plasmodium falciparum purine nucleoside phosphorylase: involvement in catalysis and microenvironment.

Among various tropical diseases, malaria is a major life-threatening disease caused by Plasmodium parasite. Plasmodium falciparum is responsible for the deadliest form of malaria, so-called cerebral malaria. Purine nucleoside phosphorylase from P. falciparum is a homohexamer containing single tryptophan residue per subunit that accepts inosine and guanosine but not adenosine for its activity. This enzyme has been exploited as drug target against malaria disease. It is important to draw together significant knowledge about inherent properties of this enzyme which will be helpful in better understanding of this drug target. The enzyme shows disorder to order transition during catalysis. The single tryptophan residue residing in conserved region of transition loop is present in purine nucleoside phosphorylases throughout the Plasmodium genus. This active site loop motif is conserved among nucleoside phosphorylases from apicomplexan parasites. Modification of tryptophan residue by N-bromosuccinamide resulted in complete loss of activity showing its importance in catalysis. Inosine was not able to protect enzyme against N-bromosuccinamide modification. Extrinsic fluorescence studies revealed that tryptophan might not be involved in substrate binding. The tryptophan residue localised in electronegative environment showed collisional and static quenching in the presence of quenchers of different polarities.