Combining empirical knowledge, in silico molecular docking and ADMET profiling to identify therapeutic phytochemicals from Brucea antidysentrica for acute myeloid leukemia

Acute myeloid leukemia (AML) is one of the deadly cancers. Chemotherapy is the first-line treatment and the only curative intervention is stem cell transplantation which are intolerable for aged and comorbid patients. Therefore, finding complementary treatment is still an active research area. For this, empirical knowledge driven search for therapeutic agents have been carried out by long and arduous wet lab processes. Nonetheless, currently there is an accumulated bioinformatics data about natural products that enabled the use of efficient and cost effective in silico methods to find drug candidates. In this work, therefore, we set out to computationally investigate the phytochemicals from Brucea antidysentrica to identify therapeutic phytochemicals for AML. We performed in silico molecular docking of compounds against AML receptors IDH2, MCL1, FLT3 and BCL2. Phytochemicals were docked to AML receptors at the same site where small molecule drugs were bound and their binding affinities were examined. In addition, random compounds from PubChem were docked with AML targets and their docking score was compared with that of phytochemicals using statistical analysis. Then, non-covalent interactions between phytochemicals and receptors were identified and visualized using discovery studio and Protein-Ligand Interaction Profiler web tool (PLIP). From the statistical analysis, most of the phytochemicals exhibited significantly lower (p-value ≤ 0.05) binding energies compared with random compounds. Using cutoff binding energy of less than or equal to one standard deviation from the mean of the phytochemicals\u27 binding energies for each receptor, 12 phytochemicals showed considerable binding affinity. Especially, hydnocarpin (-8.9 kcal/mol) and yadanzioside P (-9.4 kcal/mol) exhibited lower binding energy than approved drugs AMG176 (-8.6 kcal/mol) and gilteritinib (-9.1 kcal/mol) to receptors MCL1 and FLT3 respectively, indicating their potential to be lead molecules. In addition, most of the phytochemicals possessed acceptable drug-likeness and absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. Based on the binding affinities as exhibited by the molecular docking studies supported by the statistical analysis, 12 phytochemicals from Brucea antidysentrica (1,11-dimethoxycanthin-6-one, 1-methoxycanthin-6-one, 2-methoxycanthin-6-one, beta-carboline-1-propionic acid, bruceanol A, bruceanol D, bruceanol F, bruceantarin, bruceantin, canthin-6-one, hydnocarpin, and yadanzioside P) can be considered as candidate compounds to prevent and manage AML. However, the phytochemicals should be further studied using in vivo & in vitro experiments on AML models. Therefore, this study concludes that combination of empirical knowledge, in silico molecular docking and ADMET profiling is useful to find natural product-based drug candidates. This technique can be applied to other natural products with known empirical efficacy

Cheminformatic Approach for Deconvolution of Active Compounds in a Complex Mixture - phytoserms in Licorice

ABSTRACT After the validation of our in silico models by using the previous knowledge in this area the alerting phytochemicals from two Glycyrrhiza species (G. glabra and G. uralensis) were clustered. Exhaustive computational mining of licorice metabolome against selected endocrinal and metabolic targets led to the discovery of a unique class of compounds which belong to the dihydrostilbenoids (DHS) class appended with prenyl groups at various positions. To the best of our knowledge this interesting group of compounds has not been studied for their estrogenic activities or PXR activation. In addition some of the bis-prenylated DHS have been reported to be present only in G. uralensis. Another aspect of the current project was to predict the phase I primary metabolites of compounds found in both species of Glycyrrhiza and assess them with computational tools to predict their binding potential against both isoforms of hERs or drug metabolizing enzymes such as (CYP) inhibition models. Our investigations revealed estrogenic character for most of the predicted metabolites and have confirmed earlier reports of potential CYP3A4 and CYP1A2 inhibition. Compilation of such data is essential to gain a better understanding of the efficacy/safety of licorice extracts used in various botanical formularies. This approach with the involved cheminformatic tools has proven effective to yield rich information to support our understanding of traditional practices. It also can expand the role of botanical drugs for introducing new chemical entities (NCEs) and/or uncovering their liabilities at early stages. In this work we endeavored to comprehend the mechanism associated with the efficacy and safety of components reported in the licorice plant. We utilized smart screening techniques such as cheminformatics tools to reveal the high number of secondary metabolites produced by licorice which are capable of interfering with the human Estrogen Receptors (hERs) and/or PXR or other vital cytochrome P450 enzymes. The genus Glycyrrhiza encompasses several species exhibiting complex structural diversity of secondary metabolites and hence biological activities. The intricate nature of botanical remedies such as licorice rendered them obsolete for scientific research or medical industry. Understanding and finding the mechanisms of efficacy or safety for a plant-based therapy is very challenging yet it remains crucial and warranted. The licorice plant is known to have Selective Estrogen Receptor Modulatory effects (SERMs) with a spectrum of estrogenic and anti-estrogenic activities attributed to women’s health. On the contrary licorice extract was shown to induce pregnane xenobiotic receptor (PXR) which may manifest as a potential route for deleterious effects such as herb-drug interaction (HDI). While many studies attributed these divergent activities to a few classes of compounds such as liquiritigenin (a weak estrogenic SERM) or glycyrrhizin (weak PXR agonist) no attempt was made to characterize the complete set of compounds responsible for these divergent activities. A plethora of licorice components is undermined which might have the potential to be developed into novel phytoSERMS or to trigger undesirable adverse effects by altering drug metabolizing enzymes and thus pharmacokinetics. Thus we have ventured to synthesize a set of constitutional isomers of stilbenoids and DHS (archetypal of those found in licorice) with different prenylation patterns. Sixteen constitutional isomers of stilbenoids (M2-M10) and DHS (M12-M18) were successfully synthesized of which six of them (M8 M9 M14 M15 M17 and M18) were synthesized for the first time to be further tested and validated with cell-based methods for their estrogenic activities. We have unveiled a novel class of compounds which possess a strong PXR activation. These results which were in accord with the in silico prediction were observed for multiple synthesized prenylated stilbenoid and DHS by the luciferase reporter gene assay at µM concentrations. Moreover this activation was further validated by the six-fold increase in mRNA expression of Cytochrome P450 3A4 (CYP3A4) where three representative compounds (M7 M10 and M15) exceeded the activation fold of the positive control

Dihydroxy berberine from Tinospora cordifolia: In silico evidences for the mechanism of anti-inflammatory action through dual inhibition of Lipoxygenase and Cyclooxygenase

244-252The non-steroidal anti-inflammatory drugs in clinical use have been implicated with side effects on prolonged use. This implies the dearth of a safer alternative to these drugs and can be easily sourced from the huge resources available to us through Ayurveda. Tinospora cordifolia has been used in the preparation of traditional Ayurvedic formulations, with reported anti-inflammatory activities. Molecular docking studies have been used in an attempt to identify and elucidate the mechanism of action of the bioactive compounds in T. cordifolia with dual inhibition of 5-Lipoxygenase (5-LOX) and Cyclooxygenase-2 (COX-2) enzymes for identification of lead compounds. A screening of the compounds identified in the bioactive fraction of T. cordifolia was carried out using the drug-likeness score and the selected compounds were docked with the Glide module of Schrödinger suite 2014 with Maestro 9.3. Dihydroberberine (TC1) was found to be a potent inhibitor of both 5-Lipoxygenase and Cyclooxygenase-2 enzymes. The binding energy of the compounds to the free enzyme was better than when co-crystallized with substrate indicating preference to the enzyme active site. Dihydroberberine can be evaluated further as a promising candidate to develop a safer anti-inflammatory drug

Dihydroxy berberine from Tinospora cordifolia: In silico evidences for the mechanism of anti-inflammatory action through dual inhibition of Lipoxygenase and Cyclooxygenase

The non-steroidal anti-inflammatory drugs in clinical use have been implicated with side effects on prolonged use. This implies the dearth of a safer alternative to these drugs and can be easily sourced from the huge resources available to us through Ayurveda. Tinospora cordifolia has been used in the preparation of traditional Ayurvedic formulations, with reported anti-inflammatory activities. Molecular docking studies have been used in an attempt to identify and elucidate the mechanism of action of the bioactive compounds in T. cordifolia with dual inhibition of 5-Lipoxygenase (5-LOX) and Cyclooxygenase-2 (COX-2) enzymes for identification of lead compounds. A screening of the compounds identified in the bioactive fraction of T. cordifolia was carried out using the drug-likeness score and the selected compounds were docked with the Glide module of Schrödinger suite 2014 with Maestro 9.3. Dihydroberberine (TC1) was found to be a potent inhibitor of both 5-Lipoxygenase and Cyclooxygenase-2 enzymes. The binding energy of the compounds to the free enzyme was better than when co-crystallized with substrate indicating preference to the enzyme active site. Dihydroberberine can be evaluated further as a promising candidate to develop a safer anti-inflammatory drug

Recent advances in in silico target fishing

In silico target fishing, whose aim is to identify possible protein targets for a query molecule, is an emerging approach used in drug discovery due its wide variety of applications. This strategy allows the clarification of mechanism of action and biological activities of compounds whose target is still unknown. Moreover, target fishing can be employed for the identification of off targets of drug candidates, thus recognizing and preventing their possible adverse effects. For these reasons, target fishing has increasingly become a key approach for polypharmacology, drug repurposing, and the identification of new drug targets. While experimental target fishing can be lengthy and difficult to implement, due to the plethora of interactions that may occur for a single small-molecule with different protein targets, an in silico approach can be quicker, less expensive, more efficient for specific protein structures, and thus easier to employ. Moreover, the possibility to use it in combination with docking and virtual screening studies, as well as the increasing number of web-based tools that have been recently developed, make target fishing a more appealing method for drug discovery. It is especially worth underlining the increasing implementation of machine learning in this field, both as a main target fishing approach and as a further development of already applied strategies. This review reports on the main in silico target fishing strategies, belonging to both ligand-based and receptor-based approaches, developed and applied in the last years, with a particular attention to the different web tools freely accessible by the scientific community for performing target fishing studies

Similarity Methods in Chemoinformatics

promoting access to White Rose research paper