Computer-Aided Estimation of Biological Activity Profiles of Drug-Like Compounds Taking into Account Their Metabolism in Human Body

Filimonov, Dmitry; Rudik, Anastasia V.; Дмитриев, А. В.; Poroikov, Vladimir

doi:10.3390/ijms21207492

Cited by 22 publications

(14 citation statements)

References 41 publications

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“…The biological activity profiles of possible drug candidates must take into account human metabolism because drugs interact with several molecular targets in the body [ 61 ]. With respect to bioactivity, Strophanthidin is predicted to have the highest enzyme inhibition activity while Isopteropodin has the lowest ( Table 1 ).…”

Section: Discussionmentioning

confidence: 99%

Identifying potential natural inhibitors of Brucella melitensis Methionyl-tRNA synthetase through an in-silico approach

et al. 2022

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Background Brucellosis is an infectious disease caused by bacteria of the genus Brucella. Although it is the most common zoonosis worldwide, there are increasing reports of drug resistance and cases of relapse after long term treatment with the existing drugs of choice. This study therefore aims at identifying possible natural inhibitors of Brucella melitensis Methionyl-tRNA synthetase through an in-silico approach. Methods Using PyRx 0.8 virtual screening software, the target was docked against a library of natural compounds obtained from edible African plants. The compound, 2-({3-[(3,5-dichlorobenzyl) amino] propyl} amino) quinolin-4(1H)-one (OOU) which is a co-crystallized ligand with the target was used as the reference compound. Screening of the molecular descriptors of the compounds for bioavailability, pharmacokinetic properties, and bioactivity was performed using the SWISSADME, pkCSM, and Molinspiration web servers respectively. The Fpocket and PLIP webservers were used to perform the analyses of the binding pockets and the protein ligand interactions. Analysis of the time-resolved trajectories of the Apo and Holo forms of the target was performed using the Galaxy and MDWeb servers. Results The lead compounds, Strophanthidin and Isopteropodin are present in Corchorus olitorius and Uncaria tomentosa (Cat’s-claw) plants respectively. Isopteropodin had a binding affinity score of -8.9 kcal / ml with the target and had 17 anti-correlating residues in Pocket 1 after molecular dynamics simulation. The complex formed by Isopteropodin and the target had a total RMSD of 4.408 and a total RMSF of 9.8067. However, Strophanthidin formed 3 hydrogen bonds with the target at ILE21, GLY262 and LEU294, and induced a total RMSF of 5.4541 at Pocket 1. Conclusion Overall, Isopteropodin and Strophanthidin were found to be better drug candidates than OOU and they showed potentials to inhibit the Brucella melitensis Methionyl-tRNA synthetase at Pocket 1, hence abilities to treat brucellosis. In-vivo and in-vitro investigations are needed to further evaluate the efficacy and toxicity of the lead compounds.

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Section: Discussionmentioning

confidence: 99%

Identifying potential natural inhibitors of Brucella melitensis Methionyl-tRNA synthetase through an in-silico approach

et al. 2022

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“…The development and appropriate use of new medications necessitate an examination of their biological activity profiles, which must take into account human metabolism. This is due to the fact that most drugs interact with several or multiple molecular targets in the body, resulting in complicated bioactivity profiles [49]. With respect to bioactivity, Strophanthidin is predicted to have the highest enzyme inhibition activity while Isopteropodin has the lowest (Table 1).…”

Section: Discussionmentioning

confidence: 99%

Identifying potential natural inhibitors of Brucella melitensis Methionyl-tRNA synthetase through an in-silico approach

Rowaiye

Ogugua

Ibeanu³

et al. 2021

Preprint

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Background: Brucellosis is an infectious disease caused by bacteria of the genus Brucella. Although it is the most common zoonosis worldwide, there are increasing reports of drug resistance and cases of relapse after long term treatment with the existing drugs of choice. This study therefore aims at identifying possible natural inhibitors of Brucella melitensis Methionyl-tRNA synthetase through an in-silico approach. Methods: Using PyRx 0.8 virtual screening software, the target was docked against a library of natural compounds obtained from edible African plants. The compound, 2-({3-[(3,5-dichlorobenzyl) amino] propyl} amino) quinolin-4(1H)-one (OOU) which is a co-crystallized ligand with the target was used as the reference compound. Screening of the molecular descriptors of the compounds for bioavailability, pharmacokinetic properties, and bioactivity was performed using the SWISSADME, pkCSM, and Molinspiration web servers respectively. The Fpocket and PLIP webservers were used to perform the analyses of the binding pockets and the protein ligand interactions. Analysis of the time-resolved trajectories of the Apo and Holo forms of the target was performed using the Galaxy and MDWeb servers. The lead compounds, Strophanthidin and Isopteropodin are present in Corchorus olitorius and Uncaria tomentosa (cat-claw) plants respectively. Results: Isopteropodin had a binding affinity score of -8.9 kcal / ml with the target and had 17 anti-correlating residues in pocket 1 after molecular dynamics simulation. The complex formed by Isopteropodin and the target had a total RMSD of 4.408 and a total RMSF of 9.8067. However, Strophanthidin formed 3 hydrogen bonds with the target at ILE21, GLY262 and LEU294, and induced a total RMSF of 5.4541 at Pocket 1. Conclusion: Overall, Isopteropodin and Strophanthidin were found to be better drug candidates than OOU and they showed potentials to inhibit the Brucella melitensis Methionyl-tRNA synthetase at Pocket 1, hence abilities to treat brucellosis. In vivo and in vitro investigations are needed to further evaluate the efficacy and toxicity of the lead compounds.

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“…Another approach for considering metabolite information in toxicity prediction is the calculation of an "Overall predicted probability of toxicity" by combining the probabilities predicted for the parent compounds and their metabolites. A related approach (although based on distinct modeling methods and utilizing measured metabolites; explored for different endpoints) was applied, with some success, by Dmitriev et al 2 and Filimonov et al 3 (see the Introduction section for details).…”

Section: Combination Of Predicted Probabilities For Parent Compounds ...mentioning

confidence: 99%

Consideration of predicted small-molecule metabolites in computational toxicology

et al. 2022

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Computer-Aided Estimation of Biological Activity Profiles of Drug-Like Compounds Taking into Account Their Metabolism in Human Body

Cited by 22 publications

References 41 publications

Identifying potential natural inhibitors of Brucella melitensis Methionyl-tRNA synthetase through an in-silico approach

Identifying potential natural inhibitors of Brucella melitensis Methionyl-tRNA synthetase through an in-silico approach

Identifying potential natural inhibitors of Brucella melitensis Methionyl-tRNA synthetase through an in-silico approach

Consideration of predicted small-molecule metabolites in computational toxicology

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