Potential Epha2 Receptor Blockers Involved in Cerebral Malaria from Taraxacum officinale, Tinospora cordifolia, Rosmarinus officinalis and Ocimum basilicum: A Computational Approach (original) (raw)
Related papers
Indian Journal of Pharmaceutical Sciences, 2019
The present investigation dealt with determination of the binding affinities in silico of six limonoids from Neem, 7-deacetoxy-7-oxogedunin, 17-hydroxyazadiradione, nimolicinol, 6-acetynimbadiol, andirobin and gedunin to bind the protein kinase, pfpk5 from Plasmodium falciparum, compared to staurosporine, a well-known protein kinase inhibitor. Further, the molecules’ pharmacokinetics and toxicity was also evaluated. Among the six compounds, 7-deacetoxy-7-oxogedunin and nimolicinol showed the best binding affinity for pfpk5 via interactions of hydrogen and pi bond and were also predicted to be potent molecules. The current in silico study suggested that limonoids could be potential pfpk5 inhibitors, which could further be developed as antimalarial drugs. Going forward the in vitro and in vivo studies are needed to confirm the efficacy of limonoids as pfpk5 inhibitors.
International Journal of Molecular Sciences
Specific adhesion of P. falciparum parasite-infected erythrocytes (IE) in deep vascular beds can result in severe complications, such as cerebral malaria, placental malaria, respiratory distress, and severe anemia. Cerebral malaria and severe malaria syndromes were associated previously with sequestration of IE to a microvasculature receptor ICAM-1. The screening of Torrey Pines Scaffold Ranking library, which consists of more than 30 million compounds designed around 75 molecular scaffolds, identified small molecules that inhibit cytoadhesion of ICAM-1-binding IE to surface-immobilized receptor at IC50 range down to ~350 nM. With their low cytotoxicity toward erythrocytes and human endothelial cells, these molecules might be suitable for development into potentially effective adjunct anti-adhesion drugs to treat cerebral and/or severe malaria syndromes. Our two-step high-throughput screening approach is specifically designed to work with compound mixtures to make screening and deco...
Malaria parasites show resistance to most of the antimalarial drugs and hence developing antimalarials which can act on multitargets rather than a single target will be a promising strategy of drug design. Here we report a new approach by which virtual screening of 292 unique phytochemicals present in 72 traditionally important herbs is used for finding out inhibitors of plasmepsin-2 and falcipain-2 for antimalarial activity against P. falciparum. Initial screenings of the selected molecules by Random Forest algorithm model of Weka using the bioassay datasets AID 504850 and AID 2302 screened 120 out of the total 292 phytochemicals to be active against the targets. Toxtree scan cautioned 21 compounds to be either carcinogenic or mutagenic and were thus removed for further analysis. Out of the remaining 99 compounds, only 46 compounds offered drug-likeness as per the 'rule of five' criteria. Out of ten antimalarial drug targets, only two target proteins such as 3BPF and 3PNR of falcipain-2 and 1PFZ and 2BJU of plasmepsin-2 are selected as targets. The potential binding of the selected 46 compounds to the active sites of these four targets was analyzed using MOE software. The docked conformations and the interactions with the binding pocket residues of the target proteins were understood by 'Ligplot' analysis. It has been found that 8 compounds are dual inhibitors of falcipain-2 and plasmepsin-2, with the best binding energies. Compound 117 (6aR, 12aS)-12a-Hydroxy-9-methoxy-2,3-dimethylenedioxy-8-prenylrotenone (Usaratenoid C) present in the plant Millettia usaramensis showed maximum molecular docking score.
Molecular docking studies of antimalarial drug and its analogues against falcipain-2 protein
Two P. falciparum cysteine proteases, falcipain-2 and falcipain-3 have been characterized as hemoglobinases. Falcipain-2 plays an important role in the parasite life cycle by intracellular development of the parasite and degrading erythrocyte proteins, most notably hemoglobin. Inhibition of falcipain-2 prevents parasite maturation, suggesting these proteins may be valuable targets for the design of novel antimalarial drugs. An In silico approach using docking of the receptor site of falcipain-2 with twenty different available antimalarial drugs has been performed for prediction of potent drug target. Drug Diocopeltine A show best binding energy and interaction than other selected antimalarial drugs with the receptor protein. Four analogs of Dioncopeltine A were found from the ZINC database and by further docking study it was observed that only one (ZINC06441799) shows minimum binding energy and good interaction than other analogs. Therefore, the analog of Dioncopeltine A (ZINC064417...