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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

Plot of the physico-chemical descriptor used to predict BBB penetration. Predicted log B/B against count. The x-axis label is the lower limit of binned data, e.g. 0 is equivalent to 0.0 to 1.0. Colour codes are as defined in Figure 1.
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Fig4: Plot of the physico-chemical descriptor used to predict BBB penetration. Predicted log B/B against count. The x-axis label is the lower limit of binned data, e.g. 0 is equivalent to 0.0 to 1.0. Colour codes are as defined in Figure 1.

Mentions: Too polar drugs do not cross the BBB. The blood/brain partition coefficients (logB/B) were computed and used as a predictor for access to the central nervous system (CNS). The predicted CNS activity was computed on a −2 (inactive) to +2 (active) scale and showed that only 2.47% of the compounds in ConMedNP could be active in the CNS (predicted CNS activity > 1). A distribution of logB/B (Figure 4) shows a right-slanted Gaussian-shaped curve with a peak at −0.5 logB/B units (the same for all the standard subsets), with 88.53% of the compounds in ConMedNP falling within the recommended range for the predicted brain/blood partition coefficient (−3.0 to 1.2). Madin-Darby canine kidney (MDCK) monolayers, are widely used to make oral absorption estimates, the reason being that these cells also express transporter proteins, but only express very low levels of metabolizing enzymes (Veber et al. 2002). They are also used as an additional criterion to predict BBB penetration. Thus, our calculated apparent MDCK cell permeability could be considered to be a good mimic for the BBB (for non-active transport). It was estimated that only about 47% of the compounds had apparent MDCK cell permeabilities which fall within the recommended range of 25–500 nm s-1 for 95% of known drugs. This situation knew improvements in the “drug-like” and “lead-like” subsets (~60% for both subsets).Figure 4


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)

Plot of the physico-chemical descriptor used to predict BBB penetration. Predicted log B/B against count. The x-axis label is the lower limit of binned data, e.g. 0 is equivalent to 0.0 to 1.0. 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

Fig4: Plot of the physico-chemical descriptor used to predict BBB penetration. Predicted log B/B against count. The x-axis label is the lower limit of binned data, e.g. 0 is equivalent to 0.0 to 1.0. Colour codes are as defined in Figure 1.
Mentions: Too polar drugs do not cross the BBB. The blood/brain partition coefficients (logB/B) were computed and used as a predictor for access to the central nervous system (CNS). The predicted CNS activity was computed on a −2 (inactive) to +2 (active) scale and showed that only 2.47% of the compounds in ConMedNP could be active in the CNS (predicted CNS activity > 1). A distribution of logB/B (Figure 4) shows a right-slanted Gaussian-shaped curve with a peak at −0.5 logB/B units (the same for all the standard subsets), with 88.53% of the compounds in ConMedNP falling within the recommended range for the predicted brain/blood partition coefficient (−3.0 to 1.2). Madin-Darby canine kidney (MDCK) monolayers, are widely used to make oral absorption estimates, the reason being that these cells also express transporter proteins, but only express very low levels of metabolizing enzymes (Veber et al. 2002). They are also used as an additional criterion to predict BBB penetration. Thus, our calculated apparent MDCK cell permeability could be considered to be a good mimic for the BBB (for non-active transport). It was estimated that only about 47% of the compounds had apparent MDCK cell permeabilities which fall within the recommended range of 25–500 nm s-1 for 95% of known drugs. This situation knew improvements in the “drug-like” and “lead-like” subsets (~60% for both subsets).Figure 4

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