scholarly journals Identification of steroid-like natural products as antiplasmodial agents by 2D and 3D similarity-based virtual screening

MedChemComm ◽  
2017 ◽  
Vol 8 (6) ◽  
pp. 1152-1157 ◽  
Author(s):  
Elumalai Pavadai ◽  
Gurminder Kaur ◽  
Sergio Wittlin ◽  
Kelly Chibale
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Natural Products ◽  
Virtual Screening ◽  
Antimalarial Drugs ◽  
2D And 3D ◽  
3D Similarity

The emergence of drug resistance in Plasmodium falciparum to available antimalarial drugs has challenged current antimalarial treatments.

scholarly journals IN-SILICO SCREENING AGAINST ANTIMALARIAL TARGET PLASMODIUM FALCIPARUM ENOYL-ACYL CARRIER PROTEIN REDUCTASE

2017 ◽  
Vol 10 (17) ◽  
pp. 127
Author(s):  
Berwi Fazri Pamudi ◽  
Azizahwati Azizahwati ◽  
Arry Yanuar
Keyword(s):  
Plasmodium Falciparum ◽  
Virtual Screening ◽  
In Silico ◽  
Acyl Carrier Protein ◽  
Parasitic Infection ◽  
Antimalarial Drugs ◽  
Chemotherapeutic Agents ◽  
Effective Vaccine ◽  
Carrier Protein ◽  
In Silico Screening

  Objective: Malaria is a parasitic infection that causes worldwide health problems. The absence of an effective vaccine and Plasmodium strains that are resistant to antimalarial drugs emphasize the importance of developing new chemotherapeutic agents. The use of computers for in-silico screening, or virtual screening, is currently being developed as a method for discovering antimalarial drugs. One of the enzymes that can support the development of the malaria parasite is the Plasmodium falciparum enoyl-acyl carrier protein reductase (PfENR). Inhibition of these enzymes leads to Type II lipid biosynthesis inhibition on the parasite.Methods: This research investigates the use of virtual screening to find PfENR inhibitor candidates. A molecular docking method using GOLD software and the medicinal plants in Indonesia database will be used. This target has been optimized by the removal of residues and the addition of charge. Ligand is expected to be an inhibitor of PfENR.Results: In-silico screening, or virtual screening, found that the top five compounds with the highest GOLD score at trial are kaempferol 3-rhamnosyl- (1-3)-rhamnosyl-(1-6)-glucoside; cyanidin 3,5-di-(6-malonylglucoside); 8-hydroxyapigenin 8-(2’’, 4’’-disulfato glucuronide); epigallocatechin 3,5,-di- O-gallat; quercetin 3,4’-dimethyl ether 7-alpha-L-arabinofuranosyl-(1-6)-glucoside. They had GOLD scores of 94.73, 95.90, 86.46, 85.39, and 84.40, respectively.Conclusions: There are two candidate inhibitor compounds from tea (Camellia sinensis), which have potential for development as an antimalarial drug, which are kaempferol 3-rhamnosyl-(1-3)-rhamnosyl-(1-6)-glucoside and epigallocatechin 3,5,-di-O-gallate, with a GOLD score of 94.73 and 85.39, respectively.

scholarly journals Molecular Surveillance of Antimalarial Resistance Pfcrt, Pfmdr1 and Pfk13 Polymorphisms in African Plasmodium Falciparum Imported Parasites to Wuhan, China

2020 ◽  
Author(s):  
Cheng Weijia ◽  
Xiaonan Song ◽  
Huabing Tan ◽  
Kai Wu ◽  
Jian Li
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Mixed Type ◽  
Antimalarial Drugs ◽  
Wild Type ◽  
Mutant Type ◽  
Molecular Surveillance ◽  
Severe Problem ◽  
Antimalarial Resistance ◽  
Effective Drugs

Abstract Background: The development of drug resistance in Plasmodium falciparum becomes a severe problem for malaria control globally. Before finding a practical solution, monitoring the susceptibility of P. falciparum resistance-related genes is crucial. It will offer valuable information on the drug resistance in malaria-endemic areas and guides the rational clinical use of antimalarial drugs.Methods：Filter paper blood was taken from patients with positive P. falciparum during 2017-2019 in Wuhan, China. The target fragments from pfcrt, pfmdr1, and k13 propeller (pfk13) genes of P. falciparum were amplified and sequenced. Subsequently, the polymorphisms of pfcrt, pfmdr1, and pfk13 and the haplotypes of Pfcrt and Pfmdr1 were analyzed.Results: Totally, 106 samples were collected. Subsequently, 98.11% (104/106), 100% (106/106), and 86.79% (92/106) of these samples were successfully amplified and sequenced for the pfcrt, pfmdr1, and pfk13 genes, respectively. The prevalence of Pfcrt K76T, Pfmdr1 N86Y, and Pfmdr1 Y184F mutation were 9.62%, 4.72%, and 47.17%, respectively. At codons 72-76 of pfcrt gene locus were showed three haplotypes, including CVMNK (wild-type), CVIET (mutation type), CV M/I N/E K/T (mixed type), with 87.50%, 9.62%, and 2.88% prevalence, respectively. For the pfmdr1 gene, including NY (wild type), NF and YF (mutant type), N Y/F, Y Y/F, and N/Y Y/F (mixed type), accounted for 34.91%, 43.40%, 3.77%, 15.09%, 0.94%, and 1.89%, respectively. A total of eleven Pfcrt/Pfmdr1 combined haplotypes, including six types of combined haplotypes, and five combined haplotypes with mixed-type, For pfk13, no mutation was detected. Conclusions: The wild-type SNPs and haplotypes for the pfcrt, and pfmdr1 genes become predominant in the current study. It indicates these isolates entirely or partly recovery their susceptibility to antimalarial drugs, including chloroquine, amodiaquine, and mefloquine. Moreover, it demonstrates these drugs can continue to be effective drugs for P. falciparum malaria cases treatment in Africa. Although no mutation is detected in pfk13, continuous molecular surveillance is still urgently necessary.

scholarly journals Role ofPfmdr1inIn VitroPlasmodium falciparum Susceptibility to Chloroquine, Quinine, Monodesethylamodiaquine, Mefloquine, Lumefantrine, and Dihydroartemisinin

2014 ◽  
Vol 58 (12) ◽  
pp. 7032-7040 ◽  
Author(s):  
Nathalie Wurtz ◽  
Bécaye Fall ◽  
Aurélie Pascual ◽  
Mansour Fall ◽  
Eric Baret ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Multidrug Resistance ◽  
Antimalarial Drug ◽  
Antimalarial Drugs ◽  
Wild Type ◽  
Antimalarial Drug Resistance ◽  
Content Type ◽  
Increased Susceptibility

ABSTRACTThe involvement ofPfmdr1(Plasmodium falciparummultidrug resistance 1) polymorphisms in antimalarial drug resistance is still debated. Here, we evaluate the association between polymorphisms inPfmdr1(N86Y, Y184F, S1034C, N1042D, and D1246Y) andPfcrt(K76T) andin vitroresponses to chloroquine (CQ), mefloquine (MQ), lumefantrine (LMF), quinine (QN), monodesethylamodiaquine (MDAQ), and dihydroartemisinin (DHA) in 174Plasmodium falciparumisolates from Dakar, Senegal. ThePfmdr186Y mutation was identified in 14.9% of the samples, and the 184F mutation was identified in 71.8% of the isolates. No 1034C, 1042N, or 1246Y mutations were detected. ThePfmdr186Y mutation was significantly associated with increased susceptibility to MDAQ (P= 0.0023), LMF (P= 0.0001), DHA (P= 0.0387), and MQ (P= 0.00002). The N86Y mutation was not associated with CQ (P= 0.214) or QN (P= 0.287) responses. ThePfmdr1184F mutation was not associated with various susceptibility responses to the 6 antimalarial drugs (P= 0.168 for CQ, 0.778 for MDAQ, 0.324 for LMF, 0.961 for DHA, 0.084 for QN, and 0.298 for MQ). ThePfmdr186Y-Y184 haplotype was significantly associated with increased susceptibility to MDAQ (P= 0.0136), LMF (P= 0.0019), and MQ (P= 0.0001). The additionalPfmdr186Y mutation increased significantly thein vitrosusceptibility to MDAQ (P< 0.0001), LMF (P< 0.0001), MQ (P< 0.0001), and QN (P= 0.0026) in wild-typePfcrtK76 parasites. The additionalPfmdr186Y mutation significantly increased thein vitrosusceptibility to CQ (P= 0.0179) inPfcrt76T CQ-resistant parasites.

scholarly journals Drug Susceptibility and Genetic Evaluation of Plasmodium falciparum Isolates Obtained in Four Distinct Geographical Regions of Kenya

2004 ◽  
Vol 48 (9) ◽  
pp. 3598-3601 ◽  
Author(s):  
Abigael Mbaisi ◽  
Pamela Liyala ◽  
Fredrick Eyase ◽  
Rachel Achilla ◽  
Hosea Akala ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Drug Susceptibility ◽  
Antimalarial Drugs ◽  
Genetic Evaluation ◽  
Geographical Regions ◽  
In Vitro Drug Susceptibility

ABSTRACT The drug resistance profiles of Plasmodium falciparum isolated from four regions in Kenya were analyzed for drug resistance profiles. We observed variability in resistance to a broad range of antimalarial drugs across Kenya as determined from in vitro drug susceptibility screening and genotyping analysis.

scholarly journals Analysing the essential proteins set of Plasmodium falciparum PF3D7 for novel drug targets identification against malaria

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Fawad Ali ◽  
Hira Wali ◽  
Saadia Jan ◽  
Asad Zia ◽  
Muneeba Aslam ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Virtual Screening ◽  
Drug Targets ◽  
Human Life ◽  
Multi Drug Resistance ◽  
Essential Proteins ◽  
Human Host

Abstract Background Plasmodium falciparum is an obligate intracellular parasite of humans that causes malaria. Falciparum malaria is a major public health threat to human life responsible for high mortality. Currently, the risk of multi-drug resistance of P. falciparum is rapidly increasing. There is a need to address new anti-malarial therapeutics strategies to combat the drug-resistance threat. Methods The P. falciparum essential proteins were retrieved from the recently published studies. These proteins were initially scanned against human host and its gut microbiome proteome sets by comparative proteomics analyses. The human host non-homologs essential proteins of P. falciparum were additionally analysed for druggability potential via in silico methods to possibly identify novel therapeutic targets. Finally, the PfAp4AH target was prioritized for pharmacophore modelling based virtual screening and molecular docking analyses to identify potent inhibitors from drug-like compounds databases. Results The analyses identified six P. falciparum essential and human host non-homolog proteins that follow the key druggability features. These druggable targets have not been catalogued so far in the Drugbank repository. These prioritized proteins seem novel and promising drug targets against P. falciparum due to their key protein–protein interactions features in pathogen-specific biological pathways and to hold appropriate drug-like molecule binding pockets. The pharmacophore features based virtual screening of Pharmit resource predicted a lead compound i.e. MolPort-045–917-542 as a promising inhibitor of PfAp4AH among prioritized targets. Conclusion The prioritized protein targets may worthy to test in malarial drug discovery programme to overcome the anti-malarial resistance issues. The in-vitro and in-vivo studies might be promising for additional validation of these prioritized lists of drug targets against malaria.

scholarly journals Computer-Assisted Discovery of Alkaloids with Schistosomicidal Activity

2022 ◽  
Vol 44 (1) ◽  
pp. 383-408
Author(s):  
Renata Priscila Barros de Menezes ◽  
Jéssika de Oliveira Viana ◽  
Eugene Muratov ◽  
Luciana Scotti ◽  
Marcus Tullius Scotti
Keyword(s):  
Drug Resistance ◽  
Natural Products ◽  
Molecular Docking ◽  
Virtual Screening ◽  
Schistosoma Mansoni ◽  
In Silico ◽  
Cost Benefit ◽  
Computer Assisted ◽  
Parasitic Disease

Schistosomiasis is a chronic parasitic disease caused by trematodes of the genus Schistosoma; it is commonly caused by Schistosoma mansoni, which is transmitted by Bioamphalaria snails. Studies show that more than 200 million people are infected and that more than 90% of them live in Africa. Treatment with praziquantel has the best cost–benefit result on the market. However, hypersensitivity, allergy, and drug resistance are frequently presented after administration. From this perspective, ligand-based and structure-based virtual screening (VS) techniques were combined to select potentially active alkaloids against S. mansoni from an internal dataset (SistematX). A set of molecules with known activity against S. mansoni was selected from the ChEMBL database to create two different models with accuracy greater than 84%, enabling ligand-based VS of the alkaloid bank. Subsequently, structure-based VS was performed through molecular docking using four targets of the parasite. Finally, five consensus hits (i.e., five alkaloids with schistosomicidal potential), were selected. In addition, in silico evaluations of the metabolism, toxicity, and drug-like profile of these five selected alkaloids were carried out. Two of them, namely, 11,12-methylethylenedioxypropoxy and methyl-3-oxo-12-methoxy-n(1)-decarbomethoxy-14,15-didehydrochanofruticosinate, had plausible toxicity, metabolomics, and toxicity profiles. These two alkaloids could serve as starting points for the development of new schistosomicidal compounds based on natural products.

scholarly journals Significant Divergence in Sensitivity to Antimalarial Drugs between Neighboring Plasmodium falciparum Populations along the Eastern Border of Myanmar

2016 ◽  
Vol 61 (2) ◽  
Author(s):  
Weilin Zeng ◽  
Yao Bai ◽  
Meilian Wang ◽  
Zenglei Wang ◽  
Shuang Deng ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Antimalarial Drugs ◽  
Content Type ◽  
Border Regions ◽  
Close Proximity ◽  
Significant Divergence ◽  
Eastern Border ◽  
Parasite Populations

ABSTRACT Malaria parasites in different areas where malaria is endemic display different levels of resistance to antimalarial drugs as the result of varied drug use histories. To provide updated knowledge of drug sensitivities during the malaria elimination phase in Southeast Asia, an epicenter of multidrug resistance, we determined in vitro susceptibilities of culture-adapted Plasmodium falciparum isolates from two eastern border regions (Wa and Kachin) of Myanmar to 10 drugs. Despite their close proximity, the Kachin parasites displayed higher 50% inhibitory concentrations than the Wa parasites to chloroquine, piperaquine, naphthoquine, mefloquine, quinine, pyrimethamine, pyronaridine, lumefantrine, and dihydroartemisinin. Genotyping of genes associated with drug resistance also showed significant differences in the prevalence rates of mutant alleles between the two regions. Particularly, major pfdhfr mutations mediating pyrimethamine resistance and the pfdhps A437G mutation had significantly higher frequencies in the Kachin parasites (P < 0.005). Moreover, when pfdhfr and pfdhps were considered together, the wild-type allele was found only in the Wa samples (22.6%). In addition, the pfmdr1 Y184F mutation reached 38.7% in the Kachin parasites, compared to 9.7% in the Wa parasites, whereas N86Y was only detected in the Wa parasites, at 22.6%. Furthermore, the F446I mutation and all mutations in the propeller domain of the PfK13 gene were significantly more frequent in the Kachin parasites. Collectively, this work demonstrates that even in spatially closely separated regions, parasites can exhibit drastic differences in drug sensitivities and genetic makeups underlying drug resistance, which may reflect regionally different drug histories and genetic drift of these isolated parasite populations.

Strategy of Virtual Screening Based Discovery of HSP90 C-terminal Inhibitors and Network Pharmacological Analysis

2021 ◽  
Vol 22 ◽  
Author(s):  
Lihong Li ◽  
Man Yang ◽  
Chenyao Li ◽  
Hongyu Xue ◽  
Meiyun Shi ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Drug Resistance ◽  
Natural Products ◽  
Molecular Docking ◽  
Virtual Screening ◽  
Anticancer Agents ◽  
Binding Modes ◽  
Pharmacological Analysis ◽  
C Terminus ◽  
Anticancer Target

Background: HSP90 has been considered as an important anticancer target for several decades, but traditional HSP90 N-terminal inhibitors often suffered from organ toxicity and/or drug resistance. Methods: The development of HSP90 C-terminal inhibitors represents a reliable alternative strategy. In the view of rare examples of structure based identification of HSP90 C-terminal inhibitors, we reported a virtual screening based strategy for the discovery of HSP90 C-terminal inhibitors as anticancer agents from natural products. Results & Discussion: 13 chemical ingredients from licorice were identified as possible HSP90 inhibitors and 3 of them have been reported as anticancer agents. The binding modes of them towards HSP90 C-terminus were predicted by molecular docking and refined by molecular dynamics stimulation. Conclusion: Further network pharmacological analysis predicted overall possible targets involved in the pathways in cancer and revealed that 8 molecules possibly interact with HSP90.

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