In vitro and in vivo models used for antimalarial activity: A brief review

Rudrapal, Mithun; Chetia, Dipak

doi:10.31024/ajpp.2019.5.6.21

Cited by 2 publications

(5 citation statements)

References 15 publications

(36 reference statements)

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“…The predicted toxicity data such as LD 50 in mice and rats, Ames mutagenicity, DTP, and skin irritancy did not cross the limit of toxicity. Previous studies support the results of our present studies related to the prediction of toxicity parameters of trioxane derivatives (Rudrapal et al, 2019 ). Thus, it can be stated that the designed trioxane derivatives possess drug-likeness and ADMET properties within the acceptable range and do not have any predictive toxic features.…”

Section: Discussionsupporting

confidence: 92%

“…Moreover, docking plays an important role in the identification of bioactive molecules based on the target protein structure in RDD and discovery program (Rudrapal et al, 2018 ). The docking protocol was validated by redocking the co-crystal ligand into the predicted binding sites of the target receptor protein followed by analyzing the binding modes of the test compound in the docked complex by comparing with the binding modes of the cocrystal inhibitor E64 (Rudrapal et al, 2019 ). The cocrystallized ligand was re-docked using flexible docking simulations into the original structure of the receptor molecule by setting all the docking parameters to the software’s default values.…”

Section: Discussionmentioning

confidence: 99%

“…The ADME-Toxicity (ADMET) parameters were calculated using the ADMET descriptor protocol of DS 2020 software. Six mathematical models (aqueous solubility, blood-brain barrier penetration, cytochrome P 450 (CYP) 2D6 inhibition, hepatotoxicity, intestinal absorption, and plasma protein binding) were used for quantitative prediction of properties related to ADMET characteristics or pharmacokinetics (PKs) of drug molecules (Rudrapal et al, 2019 ).…”

Section: Methodsmentioning

confidence: 99%

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Design, molecular docking, drug-likeness, and molecular dynamics studies of 1,2,4-trioxane derivatives as novel Plasmodium falciparum falcipain-2 (FP-2) inhibitors

Ghosh¹,

Chetia²,

Gogoi³

et al. 2021

bta

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Despite significant progress made in drug discovery and development over the past few decades, malaria remains a life-threatening infectious disease across the globe. Because of the widespread emergence of drug-resistant strains of Plasmodium falciparum, the clinical utility of existing drug therapies including Artemisinin-based Combination Therapies (ACTs) in the treatment of malaria has been increasingly limited. It has become a serious health concern which, therefore, necessitates the development of novel drug molecules and/or alternative therapies to combat, particularly resistant P. falciparum. The objective of the present study was to develop 1,2,4-trioxane derivatives as novel antimalarial agents that would be effective against resistant P. falciparum. In our study, 15 new trioxane derivatives were designed by molecular modification of the 1,2,4-trioxane scaffold as possible antimalarial agents. Molecular modeling studies of trioxane derivatives were performed based on the CADD approach using Biovia Discovery Studio (DS) 2018 software. The protein-ligand docking study was performed against P. falciparum falcipain 2 (FP-2) using the simulation-based docking protocol LibDock by the flexible docking method.The assessment of drug-likeness, ADMET properties, and toxicity was also performed. Furthermore, the compounds CC3 and CC7, which showed the best binding affinity against the target P. falciparum FP-2, were investigated by molecular dynamics (MD) simulation studies followed by the calculation of MM-PBSA binding free energy of protein-ligand complexes using DS 2020. Results of the docking study showed that among the 15 compounds, three trioxane derivatives were found to possess promising binding affinity with LibDock scores ranging from 117.16 to 116.90. Drug-likeness, ADMET, and toxicity properties were found to be satisfactory for all the compounds. Among the 15 compounds, two compounds, namely CC3 and CC7, showed the highest binding affinity against FP-2 with LibDock score of 117.166 and 117.200, respectively. The Libdock score of the co-crystal inhibitor was 114.474. MD studies along with MM-PBSA calculations of binding energies further confirmed the antimalarial potential of the compounds CC3 and CC7, with the formation of well-defined and stable receptor-ligand interactions against the P. falciparum FP-2 enzyme. Additionally, the selectivity of trioxane hits identified as potential inhibitors of P. falciparum cysteine protease FP-2 was determined on human cysteine proteases such as cathepsins (Cat K and Cat L), which are host homologous. Finally, it was concluded that the newly designed 1,2,4trioxane derivatives can be further studied for in vitro and in vivo antimalarial activities for their possible development as potent antimalarial agents effective against resistant P. falciparum.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Design, molecular docking, drug-likeness, and molecular dynamics studies of 1,2,4-trioxane derivatives as novel Plasmodium falciparum falcipain-2 (FP-2) inhibitors

Ghosh¹,

Chetia²,

Gogoi³

et al. 2021

bta

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“…Compounds having high in vitro efficacy (IC 50 ≤ 1μM) and sufficient oral bioavailability can be considered for further in vivo testing. Compounds with ED 90 values of less than 10 mg/kg per os in in vivo murine model is essential for further development [12,17]. An important challenge is the lacking of efficacy in preclinical trials after the successful in vitro and in vivo studies.…”

Section: Challenges In Antimalarial Drug Discoverymentioning

confidence: 99%

“…Artemisinin-based Combination Therapies (ACTs) are currently considered as the frontline therapy against malaria caused by P. falciparum [9,10]. Due to the widespread emergence and spread of drug resistant strains of P. falciparum, the clinical utility of existing antimalarial therapies including ACTs has been drastically declined [11,12]. It has, therefore, become a serious health concern, which urgently necessities the discovery and development of novel drug candidates and/or alternative therapies for the treatment as well as prevention of resistant malaria.…”

Section: Introductionmentioning

confidence: 99%

Development of Phytomedicines as Novel Antimalarial Lead Molecules: Progress towards Successful Antimalarial Drug Discovery

Rudrapal¹,

Chetia²,

Bhattacharya³

2023

Drug Repurposing - Advances, Scopes and Opportunities in Drug Discovery

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Among numerous life-threatening infectious diseases (HIV/AIDS, TB, NTDs and EIDs), malaria continues to be the deadliest parasitic disease caused by Plasmodium protozoa transmitted by an infective female Anopheles mosquito. Plasmodium falciparum, the potentially fatal malaria parasite, is believed to be responsible for most of the morbidities and mortalities associated with malaria infections. Artemisinin-based Combination Therapies (ACTs) are currently considered to be the frontline therapy against malaria caused by P. falciparum. Despite significant progresses in antimalarial drug discovery, the control and prevention of malaria is still a challenging task. It is primarily because of the reduced clinical efficacy of existing antimalarial therapies including ACTs due to the widespread emergence of drug-resistant strains of malaria parasites, especially P. falciparum. It is, therefore, necessary to discover and develop novel drug candidates and/or alternative therapies for the treatment as well as prevention of resistant malaria. In this chapter, the potential of phytomedicines as natural sources of novel antimalarial lead molecules/ drugs with recent advances in phytomedicine-based antimalarial drug discovery has been reviewed.

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In vitro and in vivo models used for antimalarial activity: A brief review

Cited by 2 publications

References 15 publications

Design, molecular docking, drug-likeness, and molecular dynamics studies of 1,2,4-trioxane derivatives as novel Plasmodium falciparum falcipain-2 (FP-2) inhibitors

Design, molecular docking, drug-likeness, and molecular dynamics studies of 1,2,4-trioxane derivatives as novel Plasmodium falciparum falcipain-2 (FP-2) inhibitors

Development of Phytomedicines as Novel Antimalarial Lead Molecules: Progress towards Successful Antimalarial Drug Discovery

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