Combined CADD and Virtual Screening to Identify Novel Nonpeptidic Falcipain-2 Inhibitors

2020 ◽  
Vol 16 ◽  
Author(s):  
Trisha Rajguru ◽  
Dipshikha Bora ◽  
Mahendra Kumar Modi
Keyword(s):  
Plasmodium Falciparum ◽  
Life Cycle ◽  
Radius Of Gyration ◽  
Computer Aided Drug Design ◽  
Discovery Studio ◽  
Pubchem Database ◽  
Starting Point ◽  
New Type ◽  
Hemoglobin Degradation ◽  
Antimalarial Chemotherapy

Background: : Plasmodium falciparum is the most dangerous and widespread disease-causing species of malaria. Falcipain-2 (FP2) of Plasmodium falciparum, is a potential target for antimalarial chemotherapy since it is involved in an essential cellular function such as hemoglobin degradation during the parasite’s life cycle. However, despite their central role in the life cycle of the parasite, no commercial drug targeting Falcipain-2 has been developed to date. Prior efforts to develop peptide-based drugs against Plasmodium have been futile due to their susceptibility to being degraded by host enzymes. Objective:: Here we report computer-aided drug design of new nonpeptidic inhibitors against FP2, which are likely to be safe from degradation by host enzymes. Method: : We have virtually screened for the probable FP2 inhibitors from the PubChem database by submitting the wellequilibrated 3-D structure of FP2. Furthermore, virtual screenings and dockings were carried out using PyRx and Discovery Studio. Result: : We found 15 top-ranking molecules with carbaldehyde pharmacophore having a good fit with the target protein. Based on the C-Docker values, the top 4 hits (PubChem 44138738, PubChem 20983198, PubChem 20983081 and PubChem 28951461) for FP2 were identified. These four hits have been observed to bound to the active cleft of the protein. Moreover, their complexes were also found to be stable from the RMSD and Radius of Gyration analysis. Conclusion:: The selected compounds 2-(benzylamino)-8-methylquinoline-3-carbaldehyde (PubChem44138738), 6- bromo-2-(3,4-dihydro-1H-isoquinolin-2-yl)quinoline-3-carbaldehyde (PubChem 20983198), 2-(3,4-dihydro-1Hisoquinolin-2-yl)-6-ethylquinoline-3-carbaldehyde(PubChem20983081)and 2-[benzyl(methyl)amino]quinoline-3- carbaldehyde (PubChem 28951461) may be the starting point for further modification as a new type of nonpeptidic drug for malaria disease.

scholarly journals In silico identification of novel open reading frames in Plasmodium falciparum oocyte and salivary gland sporozoites using proteogenomics framework

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Sophie Gunnarsson ◽  
Sudhakaran Prabakaran
Keyword(s):  
Plasmodium Falciparum ◽  
Salivary Gland ◽  
Life Cycle ◽  
In Silico ◽  
Structure Prediction ◽  
Open Reading Frames ◽  
Biological Complexity ◽  
Ontology Term ◽  
Starting Point ◽  
Reading Frames

Abstract Background Plasmodium falciparum causes the deadliest form of malaria, which remains one of the most prevalent infectious diseases. Unfortunately, the only licensed vaccine showed limited protection and resistance to anti-malarial drug is increasing, which can be largely attributed to the biological complexity of the parasite’s life cycle. The progression from one developmental stage to another in P. falciparum involves drastic changes in gene expressions, where its infectivity to human hosts varies greatly depending on the stage. Approaches to identify candidate genes that are responsible for the development of infectivity to human hosts typically involve differential gene expression analysis between stages. However, the detection may be limited to annotated proteins and open reading frames (ORFs) predicted using restrictive criteria. Methods The above problem is particularly relevant for P. falciparum; whose genome annotation is relatively incomplete given its clinical significance. In this work, systems proteogenomics approach was used to address this challenge, as it allows computational detection of unannotated, novel Open Reading Frames (nORFs), which are neglected by conventional analyses. Two pairs of transcriptome/proteome were obtained from a previous study where one was collected in the mosquito-infectious oocyst sporozoite stage, and the other in the salivary gland sporozoite stage with human infectivity. They were then re-analysed using the proteogenomics framework to identify nORFs in each stage. Results Translational products of nORFs that map to antisense, intergenic, intronic, 3′ UTR and 5′ UTR regions, as well as alternative reading frames of canonical proteins were detected. Some of these nORFs also showed differential expression between the two life cycle stages studied. Their regulatory roles were explored through further bioinformatics analyses including the expression regulation on the parent reference genes, in silico structure prediction, and gene ontology term enrichment analysis. Conclusion The identification of nORFs in P. falciparum sporozoites highlights the biological complexity of the parasite. Although the analyses are solely computational, these results provide a starting point for further experimental validation of the existence and functional roles of these nORFs,

scholarly journals Malaria parasites both repress host CXCL10 and use it as a cue for growth acceleration

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yifat Ofir-Birin ◽  
Hila Ben Ami Pilo ◽  
Abel Cruz Camacho ◽  
Ariel Rudik ◽  
Anna Rivkin ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Life Cycle ◽  
Cerebral Malaria ◽  
Survival Strategy ◽  
Parasitic Disease ◽  
Malaria Parasites ◽  
Sensing System ◽  
Rich Domain ◽  
Cargo Delivery ◽  
Low Levels

AbstractPathogens are thought to use host molecular cues to control when to initiate life-cycle transitions, but these signals are mostly unknown, particularly for the parasitic disease malaria caused by Plasmodium falciparum. The chemokine CXCL10 is present at high levels in fatal cases of cerebral malaria patients, but is reduced in patients who survive and do not have complications. Here we show a Pf ‘decision-sensing-system’ controlled by CXCL10 concentration. High CXCL10 expression prompts P. falciparum to initiate a survival strategy via growth acceleration. Remarkably, P. falciparum inhibits CXCL10 synthesis in monocytes by disrupting the association of host ribosomes with CXCL10 transcripts. The underlying inhibition cascade involves RNA cargo delivery into monocytes that triggers RIG-I, which leads to HUR1 binding to an AU-rich domain of the CXCL10 3’UTR. These data indicate that when the parasite can no longer keep CXCL10 at low levels, it can exploit the chemokine as a cue to shift tactics and escape.

scholarly journals Interaction of Plasmodium falciparum apicortin with α- and β-tubulin is critical for parasite growth and survival

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Malabika Chakrabarti ◽  
Nishant Joshi ◽  
Geeta Kumari ◽  
Preeti Singh ◽  
Rumaisha Shoaib ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Life Cycle ◽  
Specific Protein ◽  
Parasite Growth ◽  
Growth And Survival ◽  
Apicomplexan Parasites ◽  
Parasite Replication ◽  
Main Components ◽  
Β Tubulin

AbstractCytoskeletal structures of Apicomplexan parasites are important for parasite replication, motility, invasion to the host cell and survival. Apicortin, an Apicomplexan specific protein appears to be a crucial factor in maintaining stability of the parasite cytoskeletal assemblies. However, the function of apicortin, in terms of interaction with microtubules still remains elusive. Herein, we have attempted to elucidate the function of Plasmodium falciparum apicortin by monitoring its interaction with two main components of parasite microtubular structure, α-tubulin-I and β-tubulin through in silico and in vitro studies. Further, a p25 domain binding generic drug Tamoxifen (TMX), was used to disrupt PfApicortin-tubulin interactions which led to the inhibition in growth and progression of blood stage life cycle of P. falciparum.

scholarly journals Properties of Extruded Snacks Prepared from Corn and Carrot Powder with Ascorbic Acid Addition

Processes ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 1367
Author(s):  
Valentina Obradović ◽  
Jurislav Babić ◽  
Verica Dragović-Uzelac ◽  
Antun Jozinović ◽  
Đurđica Ačkar ◽  
...  
Keyword(s):  
Ascorbic Acid ◽  
Temperature Regime ◽  
External Source ◽  
Single Screw Extruder ◽  
Functional Value ◽  
Temperature Regimes ◽  
Starting Point ◽  
Extruded Snacks ◽  
New Type ◽  
Corn Snacks

The objective of this research was to investigate the potentiality of carrot powder (CP) utilization at levels 4, 6, or 8% as ingredient of corn snacks and evaluation of the extrusion influence on functionally important ingredients such as carotenoids (color), polyphenols, fiber, fat, and antioxidant activity. The influence of ascorbic acid (AA) as an external source at levels 0.5 and 1% on this particular extrusion was also investigated. A single-screw extruder at two temperature regimes (135/170/170 °C (E1) and 100/150/150 °C (E2)) carried out extrusion. The E1 temperature regime acted favorably on total polyphenol content and crude fiber, but fat preferred the E2 regime. Extrusion, especially the E1 temperature regime, increased the extractability of carotenoids. Ascorbic acid degraded during extrusion, but it still provided protection to carotenoids and color attributes of extrudates. Snacks with increased nutritional and functional value due to carrot powder addition were successfully produced, which is a starting point for production of a new type of extruded snacks.

scholarly journals Disruption of the Plasmodium falciparum Life Cycle through Transcriptional Reprogramming by Inhibitors of Jumonji Demethylases

2020 ◽  
Vol 6 (5) ◽  
pp. 1058-1075 ◽  
Author(s):  
Krista A. Matthews ◽  
Kossi M. Senagbe ◽  
Christopher Nötzel ◽  
Christopher A. Gonzales ◽  
Xinran Tong ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Life Cycle ◽  
Transcriptional Reprogramming

scholarly journals Bhringraj Derived Phytochemicals against Pneumonia

2020 ◽  
pp. 93-96
Author(s):  
Debajani Tripathy ◽  
Chandana Adhikari ◽  
Mukundjee Pandey ◽  
Dipankar Bhattacharayay
Keyword(s):  
Molecular Docking ◽  
Life Cycle ◽  
Glutamic Acid ◽  
Interaction Energy ◽  
Plant Extract ◽  
Klebsiella Pneumonia ◽  
Discovery Studio ◽  
Docking Method ◽  
Dehydrogenase Enzyme ◽  
Molecular Docking Method

Phytochemicals from Bhringaraj plant extract are traditionally used to cure Pneumonia. It is caused by Klebsiella pneumonia. Molecular docking method applied using “Biovia Discovery Studio”. “High positive values of -CDOCKER energy and -CDOCKER interaction energy” suggested that glutamic acid can effectively deactivate the dehydrogenase enzyme, thereby interrupting the life cycle of the organism.

scholarly journals Trigonella foenum-graecum Derived Phytochemicals against Tuberculosis

2020 ◽  
pp. 121-124
Author(s):  
Bidyashree Tripathy ◽  
Elina Sahoo ◽  
Sidhartha Ray ◽  
Soumya Jal ◽  
Dipankar Bhattacharyay
Keyword(s):  
Molecular Docking ◽  
Life Cycle ◽  
Interaction Energy ◽  
Dihydrofolate Reductase ◽  
Plant Extract ◽  
Discovery Studio ◽  
Trigonella Foenum Graecum ◽  
Docking Method ◽  
Molecular Docking Method

Phytochemicals from Trigonella foenum-graecum plant extract are traditionally used to cure Tuberculosis. Molecular docking method applied using “Biovia Discovery Studio”. “High positive values of -CDOCKER energy and -CDOCKER interaction energy” suggested that this plant extract can effectively deactivate the dihydrofolate reductase enzyme thereby interrupting the life cycle of the organism.

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