Dataset Information

An in silico evaluation of the ADMET profile of the StreptomeDB database.

ABSTRACT:

Background

Computer-aided drug design (CADD) often involves virtual screening (VS) of large compound datasets and the availability of such is vital for drug discovery protocols. This paper presents an assessment of the "drug-likeness" and pharmacokinetic profile of?>?2,400 compounds of natural origin, currently available in the recently published StreptomeDB database.

Methods

The evaluation of "drug-likeness" was performed on the basis of Lipinski's "Rule of Five", while 46 computed physicochemical properties or molecular descriptors were used to predict the absorption, distribution, metabolism, elimination and toxicity (ADMET) of the compounds.

Results

This survey demonstrated that, of the computed molecular descriptors, about 28% of the compounds within the StreptomeDB database were compliant, having properties which fell within the range of ADMET properties of 95% of currently known drugs, while about 44% of the compounds had???2 violations. Moreover, about 50% of the compounds within the corresponding "drug-like" subset showed compliance, while >83% of the "drug-like" compounds had???2 violations.

Conclusions

In addition to the previously verified range of measured biological activities, the compounds in the StreptomeDB database show interesting DMPK profiles and hence could represent an important starting point for hit/lead discovery from natural sources. The generated data are available and could be highly useful for natural product lead generation programs.

SUBMITTER: Ntie-Kang F

PROVIDER: S-EPMC3736076 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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An in silico evaluation of the ADMET profile of the StreptomeDB database.

Ntie-Kang Fidele F

SpringerPlus 20130730

<h4>Background</h4>Computer-aided drug design (CADD) often involves virtual screening (VS) of large compound datasets and the availability of such is vital for drug discovery protocols. This paper presents an assessment of the "drug-likeness" and pharmacokinetic profile of > 2,400 compounds of natural origin, currently available in the recently published StreptomeDB database.<h4>Methods</h4>The evaluation of "drug-likeness" was performed on the basis of Lipinski's "Rule of Five", while 46 comput ...[more]

PMID: 23961417

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Project description:PurposeFor 30 years nature has provided a plethora of natural products with potential meaningful anti-cancer activity. Fusarochromanone (FC101a) is a small molecule fungal metabolite exhibiting potent in-vitro growth inhibitory effects and is capable of inducing apoptosis, suppressing angiogenesis and tumorigenesis, and inhibiting endothelial cell growth in multiple cancer cell lines. Despite all we know regarding FC101a, the mechanism of action and molecular target(s) of this compound have remained an enigma. Furthermore, modest in-vivo activity has been documented and requires addressing.MethodEarly stage pharmacokinetics (PK) assessment is vital to successful drug development. Herein, we aimed to use in-silico assays to i) characterize an in-depth ADMET profile of FC101a and ii) to probe for possible therapeutic targets. Two-dimensional SDF files of FC101a and 13 analogs were introduced into ADMET Predictor Version 7.1 that parses the structures in order to calculate molecular descriptors, which are used to estimate ADMET properties. Calculated ADMET values were analyzed and subjected to multiple drug-like indices, delivering a PK profile of each analog. To probe for possible targets, a total of 49 proteins were introduced into SYBYL-X Version 2.0 platform and the deepest binding pocket of each protein was virtually docked with parent compound, FC101a; with the negative control, FC101b; and with the model compound, kynurenine.ResultsEach analog showed promising ADMET qualities, although FC101 Oxazole was identified as the most optimized analog. Despite FC101a having a desirable ADME and toxicity profile, areas of concern were identified and must be addressed in-vitro. These include potential mutagenic properties and estrogen receptor toxicity. We provide potential avenues medicinal chemists could use to achieve higher effective permeation, higher blood brain barrier (BBB) penetration, and higher aqueous solubility in FC101a. Molecular docking assays revealed procaspase-8 - cFLIP(L) complex as a potential biological target and led to proposed mechanisms of action by which FC101a facilitates procaspase-8 heterodimerization, thereby increasing proteolytic activity and up regulating extrinsic apoptosis.ConclusionOur data revealed both potential mechanisms of action and a promising ADMET profile of FC101a. These attributes render FC101a a promising lead candidate for development into a low toxic anti-cancer agent effective against a broad range of cancers.

Dataset Information

An in silico evaluation of the ADMET profile of the StreptomeDB database.

Background

Methods

Results

Conclusions

Publications

An in silico evaluation of the ADMET profile of the StreptomeDB database.

Similar Datasets

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