QSAR, Docking and ADMET studies of Artemisinin derivatives for Antimalarial activity targeting Plasmepsin II, a hemoglobin-degrading enzyme from P. falciparum.

ArticleinCurrent Pharmaceutical Design · June 2012with19 Reads
Abstract
This work presents the development of quantitative structure activity relationship (QSAR) model to predict the antimalarial activity of artemisinin derivatives. The structures of the molecules are represented by chemical descriptors that encode topological, geometric, and electronic structure features. Screening through QSAR model suggested that compounds A24, A24a, A53, A54 and A62 possess significant antimalarial activity. Linear model is developed by the multiple linear regression method to link structures to their reported antimalarial activity. The correlation in terms of regression coefficient (r2) was 0.90 and prediction accuracy of model in terms of cross validation regression coefficient (rCV2) was 0.82. This study indicates that chemical properties viz., atom count (all atoms), connectivity index (order 1, standard), ring count (all rings), shape index (basic kappa, order 2), and solvent accessibility surface area are well correlated with antimalarial activity. The docking study showed high binding affinity of predicted active compounds against antimalarial target Plasmepsins (Plm-II). Further studies for oral bioavailability, ADMET and toxicity risk assessment suggest that compound A24, A24a, A53, A54, A62 and A64 exhibits marked antimalarial activity comparable to standard antimalarial drugs. Later one of the predicted active compound A64 chemically synthesized, structure elucidated by NMR and in vivo tested in multidrug resistant strain of Plasmodium yoelii nigeriensis infected mice.
    • "Qidwai et al. [113] reported a QSAR model for artemisinin derivatives (96) as plasmepsin II inhibitors for antimalarial activity. The developed model proved to be robust with a noncross validated r 2 ncv 0.90 and predicted accuracy r 2 pred of 0.82. "
    [Show abstract] [Hide abstract] ABSTRACT: Among the various parasitic diseases, malaria is the deadliest one. Due to the emergence of high drug resistance to the existing drug candidates there is a global need for development of new drug candidates which will be effective against resistant strains of malaria parasite. In silico molecular modeling approaches have been playing an important role in the discovery of novel lead molecules having antimalarial activity. Present review is an effort to cover all the developments related to the application of computational techniques for the design and discovery of novel antimalarial compounds since the year 2011 onwards.
    Article · Dec 2014
    • "Recent studies have paved the way for identifying valuable leads [9], which could be useful for anti-malarial aspects as there is a persistent urge for novel compounds that can act at therapeutic targets. P. falciparum lactate dehydrogenase enzyme (pfLDH) represents one of such potential molecular target. "
    [Show abstract] [Hide abstract] ABSTRACT: Malaria is one of the most prevailing fatal diseases causing between 1.2 and 2.7 million deaths all over the world each year. Further, development of resistance against the frontline anti-malarial drugs has created an alarming situation, which requires intensive drug discovery to develop new, more effective, affordable and accessible anti-malarial agents possessing novel modes of action. Over the past few years triterpenoids from higher plants have shown a wide range of anti-malarial activities. As a part of our drug discovery program for anti-malarial agents from Indian medicinal plants, roots of Glycyrrhizaglabra were chemically investigated, which resulted in the isolation and characterization of 18β-glycyrrhetinic acid (GA) as a major constituent. The in vitro studies against P. falciparum showed significant (IC50 1.69µg/ml) anti-malarial potential for GA. Similarly, the molecular docking studies showed adequate docking (LibDock) score of 71.18 for GA and 131.15 for standard anti-malarial drug chloroquine. Further, in silico pharmacokinetic and drug-likeness studies showed that GA possesses drug-like properties. Finally, in vivo evaluation showed a dose dependent anti-malarial activity ranging from 68-100% at doses of 62.5-250mg/kg on day 8. To the best of our knowledge this is the first ever report on the anti-malarial potential of GA. Further work on optimization of the anti-malarial lead is under progress.
    Full-text · Article · Sep 2013
    • "Intracellular heme seems to be the physiologically relevant mediator of artemisinine action (Zhang and Gerhard, 2009). A relevant target protein is plasmepsin II, a heme degrading enzyme of Plasmodium sp., as shown in a QSAR study supported by in vitro and in vivo tests of the screened compounds (Qidwai et al., 2012 ). Besides Plasmodium sp., artemisinin inhibits proliferation of N. caninum, an apicomplexan closely related to T. gondii, in Vero cells with little or no host-cell toxicity (Kim et al., 2002). "
    [Show abstract] [Hide abstract] ABSTRACT: Antiparasitic chemotherapy is an important issue for drug development. Traditionally, novel compounds with antiprotozoan activities have been identified by screening of compound libraries in high-throughput systems. More recently developed approaches employ target-based drug design supported by genomics and proteomics of protozoan parasites. In this chapter, the drug targets in protozoan parasites are reviewed. The gene-expression machinery has been among the first targets for antiparasitic drugs and is still under investigation as a target for novel compounds. Other targets include cytoskeletal proteins, proteins involved in intracellular signaling, membranes, and enzymes participating in intermediary metabolism. In apicomplexan parasites, the apicoplast is a suitable target for established and novel drugs. Some drugs act on multiple subcellular targets. Drugs with nitro groups generate free radicals under anaerobic growth conditions, and drugs with peroxide groups generate radicals under aerobic growth conditions, both affecting multiple cellular pathways. Mefloquine and thiazolides are presented as examples for antiprotozoan compounds with multiple (side) effects. The classic approach of drug discovery employing high-throughput physiological screenings followed by identification of drug targets has yielded the mainstream of current antiprotozoal drugs. Target-based drug design supported by genomics and proteomics of protozoan parasites has not produced any antiparasitic drug so far. The reason for this is discussed and a synthesis of both methods is proposed.
    Full-text · Article · Jan 2013
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