Use of in-silico assays to characterize the ADMET profile and identify potential therapeutic targets of fusarochromanone, a novel anti-cancer agent

Abstract

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s40203-015-0010-5) contains supplementary material, which is available to authorized users.

Wogonin Suppresses the Activity of Matrix Metalloproteinase-9 and Inhibits Migration and Invasion in Human Hepatocellular Carcinoma

“…A total of 123 candidate proteins related with cancer metastasis were shown in Supplementary Table S1 . Before the docking process, the protein crystallographic structures were downloaded from RCSB Protein Data Bank ( ) and prepared with Sybyl-X 2.0 (Tripos, St. Louis, MO, USA) for the flexible docking studies [ 29 ]. An energy minimized 3D structure of Wogonin (PubChem: 5281703) was optimized from NCBI-PubChem ( ).…”

Exploring the Mechanism of Danshen against Myelofibrosis by Network Pharmacology and Molecular Docking

“…All protein-ligand complexes with crystal structures of the above-mentioned 5 targeted proteins were directly obtained from the RCSB Protein Data Bank (http://www.rcsb.org/pdb/home/home.do, last accessed Dec 27, 2016). For improving the accuracy of results, the conduct of docking used SYBYL-X software and systemsDock (http://systemsdock.unit.oist.jp/iddp/home/index/) [20]. SYBYL-X, as well as systemsDock, is based on network pharmacology prediction and analysis that allows docking simulations and molecular pathway maps to fully characterize ligand selectivity and to interpret the role of ligands in complex molecular networks [18].…”

A Network Pharmacology-Based Study on the Hepatoprotective Effect of Fructus Schisandrae

“…All the docking studies were carried out using the protein–ligand complexes with crystal structures. Prior to the docking studies, the protein structures were prepared with Sybyl-X version 2.0 software (Tripos Associates Inc., St. Louis, MO, USA) [ 51 ]. The preparation work includes affixing hydrogen atoms and removing co-crystallized ligands as well as water molecules from the protein–ligand complexes.…”