Botanical description, bioactivity guided isolation and in silico mode of action of anti-diabetic constituents of Pterocarpus dalbergioides flowers

To date, Plasmodium falciparum is one of the most lethal strains of the malaria parasite. P. falciparum lacks the required enzymes to create its own purines via the de novo pathway, thereby making Plasmodium falciparum hypoxanthine-guanine-xanthine phosphoribosyltransferase (PfHGXPT) a crucial enzyme in the malaria life cycle. Recently, studies have described iso-mukaadial acetate and ursolic acid acetate as promising antimalarials. However, the mode of action is still unknown, thus, the current study sought to investigate the selective inhibitory and binding actions of iso-mukaadial acetate and ursolic acid acetate against recombinant PfHGXPT using in-silico and experimental approaches. Recombinant PfHGXPT protein was expressed using E. coli BL21 cells and homogeneously purified by affinity chromatography. Experimentally, iso-mukaadial acetate and ursolic acid acetate, respectively, demonstrated direct inhibitory activity towards PfHGXPT in a dose-dependent manner. The binding affinity of iso-mukaadial acetate and ursolic acid acetate on the PfHGXPT dissociation constant (KD), where it was found that 0.0833 µM and 2.8396 µM, respectively, are indicative of strong binding. The mode of action for the observed antimalarial activity was further established by a molecular docking study. The molecular docking and dynamics simulations show specific interactions and high affinity within the binding pocket of Plasmodium falciparum and human hypoxanthine-guanine phosphoribosyl transferases. The predicted in silico absorption, distribution, metabolism and excretion/toxicity (ADME/T) properties predicted that the iso-mukaadial acetate ligand may follow the criteria for orally active drugs. The theoretical calculation derived from ADME, molecular docking and dynamics provide in-depth information into the structural basis, specific bonding and non-bonding interactions governing the inhibition of malarial. Taken together, these findings provide a basis for the recommendation of iso-mukaadial acetate and ursolic acid acetate as high-affinity ligands and drug candidates against PfHGXPT.

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Toward Understanding the Cold, Hot, and Neutral Nature of Chinese Medicines Using in Silico Mode-of-Action Analysis

Journal of Chemical Information and Modeling ◽

10.1021/acs.jcim.6b00725 ◽

2017 ◽

Vol 57 (3) ◽

pp. 468-483 ◽

Cited By ~ 14

Author(s):

Xianjun Fu ◽

Lewis H. Mervin ◽

Xuebo Li ◽

Huayun Yu ◽

Jiaoyang Li ◽

...

Keyword(s):

Mode Of Action ◽

In Silico ◽

Chinese Medicines ◽

Action Analysis

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Understanding the cellular mode of action of vernakalant using a computational model: answers and new questions

Current Directions in Biomedical Engineering ◽

10.1515/cdbme-2015-0101 ◽

2015 ◽

Vol 1 (1) ◽

pp. 418-422 ◽

Cited By ~ 1

Author(s):

Axel Loewe ◽

Yan Xu ◽

Eberhard P. Scholz ◽

Olaf Dössel ◽

Gunnar Seemann

Keyword(s):

Mode Of Action ◽

In Silico ◽

Antiarrhythmic Agent ◽

Current Knowledge ◽

Tissue Level ◽

System Level ◽

Channel Block ◽

Dose Frequency ◽

Drug Induced ◽

Level Data

AbstractVernakalant is a new antiarrhythmic agent for the treatment of atrial fibrillation. While it has proven to be effective in a large share of patients in clinical studies, its underlying mode of action is not fully understood. In this work, we aim to link experimental data from the subcellular, tissue, and system level using an in-silico approach. A Hill’s equation-based drug model was extended to cover the frequency dependence of sodium channel block. Two model variants were investigated: M1 based on subcellular data and M2 based on tissue level data. 6 action potential (AP) markers were evaluated regarding their dose, frequency and substrate dependence. M1 comprising potassium, sodium, and calcium channel block reproduced the reported prolongation of the refractory period. M2 not including the effects on potassium channels reproduced reported AP morphology changes on the other hand. The experimentally observed increase of ERP accompanied by a shortening of APD90 was not reproduced. Thus, explanations for the drug-induced changes are provided while none of the models can explain the effects in their entirety. These results foster the understanding of vernakalant’s cellular mode of action and point out relevant gaps in our current knowledge to be addressed in future in-silico and experimental research on this aspiring antiarrhythmic agent.

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In silico Investigations of the Mode of Action of Novel Colchicine Derivatives Targeting β-Tubulin Isotypes: A Search for a Selective and Specific β-III Tubulin Ligand

Frontiers in Chemistry ◽

10.3389/fchem.2020.00108 ◽

2020 ◽

Vol 8 ◽

Author(s):

Lorenzo Pallante ◽

Antonio Rocca ◽

Greta Klejborowska ◽

Adam Huczynski ◽

Gianvito Grasso ◽

...

Keyword(s):

Mode Of Action ◽

In Silico ◽

Tubulin Isotypes ◽

Colchicine Derivatives ◽

Β Tubulin

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Multiple-targets Directed Screening of Flavonoid Compounds from Citrus Species to find out Antimalarial Lead with Predicted Mode of Action: An In Silico and Whole Cell-based In vitro Approach

Current Computer - Aided Drug Design ◽

10.2174/1573409916666191226103000 ◽

2019 ◽

Vol 16 ◽

Cited By ~ 3

Author(s):

Neelutpal Gogoi ◽

Dipak Chetia ◽

Bhaskarjyoti Gogoi ◽

Aparoop Das

Keyword(s):

Mode Of Action ◽

In Silico ◽

Density Functional ◽

Chemotherapeutic Agents ◽

In Vitro Screening ◽

Citrus Species ◽

Traditional Use ◽

Discovery Studio ◽

Development Of Resistance

Background: Development of resistance by the malaria parasite Plasmodium falciparum has created challenges in the eradication of this deadly infectious disease. Hence newer strategies are adopted to combat this disease and simultaneously new lead/hit identification is going on worldwide to develop new chemotherapeutic agents against malaria. Objective: In this study, 44 flavonoids found mainly in the fruit juice of Citrus species having traditional use in malaria-associated fever were selected for in silico multiple-target directed screening against three vital targets of the parasite namely dihydrooroate dehydrogenase (PfDHODH), dihydrofolate reductase thymidine synthase (PfDHFR-TS) and plasma membrane P-type cation translocating ATPase (PfATP4) to find out new lead molecule(s). Methods: The in silico screening was carried out using different protocols of the Biovia Discovery Studio 2018 software and Network analyzer plugin of Cytoscape 3.6.0 followed by in vitro screening of the best lead. Results: After the screening, CF8 or luteolin was found to have good binding affinity against PfDHODH and PfATP4 with –CDocker energy 42.2719 and 33.1447 with respect to their co-crystal ligands. These findings were also supported by Structure-based Pharmacophore, DFT (Density Functional Theory) study and finally by in vitro screening of the lead with IC50 value 8.23 µm and 12.41 µm against 3D7 (chloroquine-sensitive) and RKL-9 (chloroquine-resistant) strain of P. falciparum respectively. Conclusion: Our study has found out a moderately active lead molecule with the predicted mode of action which can be utilized to design some new derivatives with more safety and efficacy by targeting the two enzymes.

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