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In silico drug metabolism and pharmacokinetic profiles of natural products from medicinal plants in the Congo basin.

Ntie-Kang F, Lifongo LL, Mbah JA, Owono Owono LC, Megnassan E, Mbaze LM, Judson PN, Sippl W, Efange SM - In Silico Pharmacol (2013)

Bottom Line: Material from some of the plant sources are currently employed in African Traditional Medicine.This survey demonstrated that about 45% of the compounds within the ConMedNP compound library are compliant, having properties which fall within the range of ADME properties of 95% of currently known drugs, while about 69% of the compounds have ≤ 2 violations.Moreover, about 73% of the compounds within the corresponding "drug-like" subset showed compliance.

View Article: PubMed Central - PubMed

Affiliation: CEPAMOQ, Faculty of Science, University of Douala, P.O. Box 8580, Douala, Cameroon ; Chemical and Bioactivity Information Centre, Department of Chemistry, Faculty of Science, University of Buea, P.O. Box 63, Buea, Cameroon ; Department of Pharmaceutical Sciences, Martin-Luther University of Halle-Wittenberg, Wolfgang-Langenbeck Str. 4, 06120 Halle (Saale), Germany.

ABSTRACT

Purpose: Drug metabolism and pharmacokinetics (DMPK) assessment has come to occupy a place of interest during the early stages of drug discovery today. The use of computer modelling to predict the DMPK and toxicity properties of a natural product library derived from medicinal plants from Central Africa (named ConMedNP). Material from some of the plant sources are currently employed in African Traditional Medicine.

Methods: Computer-based methods are slowly gaining ground in this area and are often used as preliminary criteria for the elimination of compounds likely to present uninteresting pharmacokinetic profiles and unacceptable levels of toxicity from the list of potential drug candidates, hence cutting down the cost of discovery of a drug. In the present study, we present an in silico assessment of the DMPK and toxicity profile of a natural product library containing ~3,200 compounds, derived from 379 species of medicinal plants from 10 countries in the Congo Basin forests and savannas, which have been published in the literature. In this analysis, we have used 46 computed physico-chemical properties or molecular descriptors to predict the absorption, distribution, metabolism and elimination and toxicity (ADMET) of the compounds.

Results: This survey demonstrated that about 45% of the compounds within the ConMedNP compound library are compliant, having properties which fall within the range of ADME properties of 95% of currently known drugs, while about 69% of the compounds have ≤ 2 violations. Moreover, about 73% of the compounds within the corresponding "drug-like" subset showed compliance.

Conclusions: In addition to the verified levels of "drug-likeness", diversity and the wide range of measured biological activities, the compounds from medicinal plants in Central Africa show interesting DMPK profiles and hence could represent an important starting point for hit/lead discovery.

No MeSH data available.


Related in: MedlinePlus

A plot of predicted logHERG values for ConMedNP and standard subsets. Colour codes are as defined in Figure 1.
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Fig8: A plot of predicted logHERG values for ConMedNP and standard subsets. Colour codes are as defined in Figure 1.

Mentions: Human ether-a-go-go related gene (HERG) encodes a potassium ion (K+) channel that is implicated in the fatal arrhythmia known as torsade de pointes or the long QT syndrome (Hedley et al. 2009). The HERG K+ channel, which is best known for its contribution to the electrical activity of the heart that coordinates the heart’s beating, appears to be the molecular target responsible for the cardiac toxicity of a wide range of therapeutic drugs (Vandenberg 2001). HERG has also been associated with modulating the functions of some cells of the nervous system and with establishing and maintaining cancer-like features in leukemic cells (Chiesa et al. 1997). Thus, HERG K+ channel blockers are potentially toxic and the predicted IC50 values often provide reasonable predictions for cardiac toxicity of drugs in the early stages of drug discovery (Aronov 2005). In this work, the estimated or predicted IC50 values for blockage of this channel have been used to model the process in silico. The recommended range for predicted log IC50 values for blockage of HERG K+ channels (logHERG) is > −5. A distribution curve for the variation of the predicted logHERG is shown in Figure 8, which is a left-slanted Gaussian-shaped curve, with a peak at −5.5 logHERG units for the total library, as well as for the “drug-like” and “lead-like” subsets. It was observed that in general, this parameter is predicted to fall within the recommended range for about 58% of the compounds within the ConMedNP dataset, ~64% for the “drug-like” subset and ~76% for the “lead-like” subset.Figure 8


In silico drug metabolism and pharmacokinetic profiles of natural products from medicinal plants in the Congo basin.

Ntie-Kang F, Lifongo LL, Mbah JA, Owono Owono LC, Megnassan E, Mbaze LM, Judson PN, Sippl W, Efange SM - In Silico Pharmacol (2013)

A plot of predicted logHERG values for ConMedNP and standard subsets. Colour codes are as defined in Figure 1.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4230438&req=5

Fig8: A plot of predicted logHERG values for ConMedNP and standard subsets. Colour codes are as defined in Figure 1.
Mentions: Human ether-a-go-go related gene (HERG) encodes a potassium ion (K+) channel that is implicated in the fatal arrhythmia known as torsade de pointes or the long QT syndrome (Hedley et al. 2009). The HERG K+ channel, which is best known for its contribution to the electrical activity of the heart that coordinates the heart’s beating, appears to be the molecular target responsible for the cardiac toxicity of a wide range of therapeutic drugs (Vandenberg 2001). HERG has also been associated with modulating the functions of some cells of the nervous system and with establishing and maintaining cancer-like features in leukemic cells (Chiesa et al. 1997). Thus, HERG K+ channel blockers are potentially toxic and the predicted IC50 values often provide reasonable predictions for cardiac toxicity of drugs in the early stages of drug discovery (Aronov 2005). In this work, the estimated or predicted IC50 values for blockage of this channel have been used to model the process in silico. The recommended range for predicted log IC50 values for blockage of HERG K+ channels (logHERG) is > −5. A distribution curve for the variation of the predicted logHERG is shown in Figure 8, which is a left-slanted Gaussian-shaped curve, with a peak at −5.5 logHERG units for the total library, as well as for the “drug-like” and “lead-like” subsets. It was observed that in general, this parameter is predicted to fall within the recommended range for about 58% of the compounds within the ConMedNP dataset, ~64% for the “drug-like” subset and ~76% for the “lead-like” subset.Figure 8

Bottom Line: Material from some of the plant sources are currently employed in African Traditional Medicine.This survey demonstrated that about 45% of the compounds within the ConMedNP compound library are compliant, having properties which fall within the range of ADME properties of 95% of currently known drugs, while about 69% of the compounds have ≤ 2 violations.Moreover, about 73% of the compounds within the corresponding "drug-like" subset showed compliance.

View Article: PubMed Central - PubMed

Affiliation: CEPAMOQ, Faculty of Science, University of Douala, P.O. Box 8580, Douala, Cameroon ; Chemical and Bioactivity Information Centre, Department of Chemistry, Faculty of Science, University of Buea, P.O. Box 63, Buea, Cameroon ; Department of Pharmaceutical Sciences, Martin-Luther University of Halle-Wittenberg, Wolfgang-Langenbeck Str. 4, 06120 Halle (Saale), Germany.

ABSTRACT

Purpose: Drug metabolism and pharmacokinetics (DMPK) assessment has come to occupy a place of interest during the early stages of drug discovery today. The use of computer modelling to predict the DMPK and toxicity properties of a natural product library derived from medicinal plants from Central Africa (named ConMedNP). Material from some of the plant sources are currently employed in African Traditional Medicine.

Methods: Computer-based methods are slowly gaining ground in this area and are often used as preliminary criteria for the elimination of compounds likely to present uninteresting pharmacokinetic profiles and unacceptable levels of toxicity from the list of potential drug candidates, hence cutting down the cost of discovery of a drug. In the present study, we present an in silico assessment of the DMPK and toxicity profile of a natural product library containing ~3,200 compounds, derived from 379 species of medicinal plants from 10 countries in the Congo Basin forests and savannas, which have been published in the literature. In this analysis, we have used 46 computed physico-chemical properties or molecular descriptors to predict the absorption, distribution, metabolism and elimination and toxicity (ADMET) of the compounds.

Results: This survey demonstrated that about 45% of the compounds within the ConMedNP compound library are compliant, having properties which fall within the range of ADME properties of 95% of currently known drugs, while about 69% of the compounds have ≤ 2 violations. Moreover, about 73% of the compounds within the corresponding "drug-like" subset showed compliance.

Conclusions: In addition to the verified levels of "drug-likeness", diversity and the wide range of measured biological activities, the compounds from medicinal plants in Central Africa show interesting DMPK profiles and hence could represent an important starting point for hit/lead discovery.

No MeSH data available.


Related in: MedlinePlus