scholarly journals Homology Modeling, Docking, Absorption, Distribution, Metabolism, Excretion and Toxicity Studies and Prediction of Deleterious Non-Synonymous Single Nucleotide Polymorphisms (Nssnps) of Thiamin Phosphate Synthase: A Potential Drug Target in Plasmodium Falciparum

2020 ◽  
Vol 82 (4) ◽  
Author(s):  
S. K. SINGH ◽  
M.S. REDDY
Keyword(s):  
Plasmodium Falciparum ◽  
Single Nucleotide Polymorphisms ◽  
Homology Modeling ◽  
Drug Target ◽  
Potential Drug Target ◽  
Nucleotide Polymorphisms ◽  
Potential Drug ◽  
Single Nucleotide ◽  
Toxicity Studies ◽  
Thiamin Phosphate Synthase

Associations between varied susceptibilities of PfATP4 inhibitors and genotypes in Ugandan Plasmodium falciparum isolates

2021 ◽  
Author(s):  
Oriana Kreutzfeld ◽  
Stephanie A. Rasmussen ◽  
Aarti A. Ramanathan ◽  
Patrick K. Tumwebaze ◽  
Oswald Byaruhanga ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Single Nucleotide Polymorphisms ◽  
Ex Vivo ◽  
Nucleotide Polymorphisms ◽  
Wild Type ◽  
Single Nucleotide ◽  
Field Isolates ◽  
Frequent Mutations ◽  
Mixed Field ◽  
P Type

Among novel compounds under recent investigation as potential new antimalarial drugs are three independently developed inhibitors of the Plasmodium falciparum P-type ATPase (PfATP4): KAE609 (cipargamin), PA92, and SJ733. We assessed ex vivo susceptibilities to these compounds of 374 fresh P. falciparum isolates collected in Tororo and Busia districts, Uganda from 2016-2019. Median IC 50 s were 65 nM for SJ733, 9.1 nM for PA92, and 0.5 nM for KAE609. Sequencing of pfatp4 for 218 of these isolates demonstrated many non-synonymous single nucleotide polymorphisms; the most frequent mutations were G1128R (69% of isolates mixed or mutant), Q1081K/R (68%), G223S (25%), N1045K (16%) and D1116G/N/Y (16%). The G223S mutation was associated with decreased susceptibility to SJ733, PA92 and KAE609. The D1116G/N/Y mutations were associated with decreased susceptibility to SJ733, and the presence of mutations at both codons 223 and 1116 was associated with decreased susceptibility to PA92 and SJ733. In all of these cases, absolute differences in susceptibilities of wild type (WT) and mutant parasites were modest. Analysis of clones separated from mixed field isolates consistently identified mutant clones as less susceptible than WT. Analysis of isolates from other sites demonstrated presence of the G223S and D1116G/N/Y mutations across Uganda. Our results indicate that malaria parasites circulating in Uganda have a number of polymorphisms in PfATP4 and that modestly decreased susceptibility to PfATP4 inhibitors is associated with some mutations now present in Ugandan parasites.

scholarly journals Single nucleotide polymorphisms in Plasmodium falciparum V type H+ pyrophosphatase gene (pfvp2) and their associations with pfcrt and pfmdr1 polymorphisms

2014 ◽  
Vol 24 ◽  
pp. 111-115 ◽  
Author(s):  
Irina Tatiana Jovel ◽  
Pedro Eduardo Ferreira ◽  
Maria Isabel Veiga ◽  
Maja Malmberg ◽  
Andreas Mårtensson ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Single Nucleotide Polymorphisms ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide

The selenoproteome of the malarial parasite Plasmodium falciparum as potential drug target

2006 ◽  
Vol 2006 (Spring) ◽  
Author(s):  
Rimma Iozef ◽  
Beate Hecker ◽  
Stefan Rahlfs ◽  
Alexey V. Lobanov ◽  
Stephan Gromer ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Drug Target ◽  
Malarial Parasite ◽  
Potential Drug Target ◽  
Potential Drug ◽  
Parasite Plasmodium ◽  
Parasite Plasmodium Falciparum

scholarly journals Binding site identification of COVID-19 main protease 3D structure by homology modeling

2021 ◽  
Vol 21 (3) ◽  
pp. 1713
Author(s):  
Marion Adebiyi ◽  
Oludayo O. Olugbara
Keyword(s):  
Secondary Structure ◽  
Homology Modeling ◽  
Binding Site ◽  
Drug Target ◽  
3D Structure ◽  
Random Coil ◽  
Local Alignment ◽  
Potential Drug Target ◽  
Potential Drug ◽  
Main Protease

The influx of coronavirus in 2019 (COVID-19) from Wuhan of China has led to a global pandemic, undesirable hiatus, and recorded millions of infection cases with several deaths worldwide. The strain of COVID-19 has neither known treatments nor vaccines, but recent studies have shown that a few of its enzymes may have been considered as potential drug target. Since its influx, the virus has been well-studied, but a lot is not known about its protease yet.  The purpose of this work was to identify the binding site in-silico and present 3D structure of COVID-19 main protease (Mpro) by homology modeling through multiple alignment followed by optimization and validation. The modeling was done by Swiss-Model template library and basic local alignment search tool (BLAST). The obtained homotrimer oligo-state model was verified for reliability using structural validation software such as PROCHECK, Verify3D, MolProbity and QMEAN. The HHBlits software was used to determine the structures that matched the target sequence by evolution. Best template, 6u7h.1.A was used to build a tertiary structure for Mpro with ProMod3 3.0.0 on the Swiss-Model workspace. Self-optimized prediction method with alignment (SOPMA) was applied to compute features of the secondary structure. The verification of quality of COVID-19 structure through Ramachandran plot showed an abundance of 99.3% of amino acid residues in allowed regions while 0.1% in disallowed region. The Verify3D rated the structure a 90.87% PASS of residues having an average 3D-1D score of at least 0.2, which validates a good environment profile for the COVID-19 Mpro model. The features of the secondary structure indicated that the modeled 3D structure of Mpro contains 32.05% α-helix and 37.17% random coil with 25.92 extended strand. DeepSite algorithm elucidates the binding site area that captured local patterns in the structure and exposed the surface cavity of the binding pocket of this protein. The main result of this study suggests that blocking expression of the protein may constitute an efficient approach for transmission blockage. Hence, our thought is that Mpro of COVID-19 may be considered a potential drug target. Nevertheless, more experimental analyses, verification and validation experiments will be required as a targeted drug or vaccine design against COVID-19 virus.

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