•A framework to perform inverse docking was developed.•Different strategies to distribute the docking procedure were implemented.•Validation with experimental complex have been done.•A docking test ...of one ligand versus 100 proteins was performed.•A better conformational sampling is processed than current methods.
Molecular docking is a widely used computational technique that allows studying structure-based interactions complexes between biological objects at the molecular scale. The purpose of the current work is to develop a set of tools that allows performing inverse docking, i.e., to test at a large scale a chemical ligand on a large dataset of proteins, which has several applications on the field of drug research. We developed different strategies to parallelize/distribute the docking procedure, as a way to efficiently exploit the computational performance of multi-core and multi-machine (cluster) environments. The experiments conducted to compare these different strategies encourage the search for decomposing strategies since it improves the execution of inverse docking.
Triptolide (TPL) is proposed as an effective anticancer agent known for its anti-proliferation of a variety of cancer cells including ovarian cancer cells. Although some studies have been conducted, ...the mechanism by which TPL acts on ovarian cancer remains to be clearly described. Herein, systematic work based on bioinformatics was carried out to discover the potential targets of TPL in SKOV-3 cells. TPL induces the early apoptosis of SKOV-3 cells in a dose- and time-dependent manner with an IC
= 40 ± 0.89 nM when cells are incubated for 48 h. Moreover, 20 nM TPL significantly promotes early apoptosis at a rate of 40.73%. Using a self-designed inverse molecular docking protocol, we fish the top 19 probable targets of TPL from the target library, which was built on 2,250 proteins extracted from the Protein Data Bank. The 2D-DIGE assay reveals that the expression of eight genes is affected by TPL. The results of western blotting and qRT-PCR assay suggest that 40 nM of TPL up-regulates the level of Annexin A5 (6.34 ± 0.07 fold) and ATP syn thase (4.08 ± 0.08 fold) and down-regulates the level of β-Tubulin (0.11 ± 0.12 fold) and HSP90 (0.21 ± 0.09 fold). More details of TPL affecting on Annexin A5 signaling pathway will be discovered in the future. Our results define some potential targets of TPL, with the hope that this agent could be used as therapy for the preclinical treatment of ovarian cancer.
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► A new scoring function was used to enhance to the accuracy of inverse docking. ► The agent Ro 48-8071 was found for the first time to selectively reduce the viability of breast ...cancer cells that express mutant p53. ► Ro 48-8071 increases p53-DNA binding in mutant p53 cancer cells. ► Oxidosqualene cyclase is a potential anti-cancer target.
Inverse docking is a relatively new technique that has been used to identify potential receptor targets of small molecules. Our docking software package MDock is well suited for such an application as it is both computationally efficient, yet simultaneously shows adequate results in binding affinity predictions and enrichment tests. As a validation study, we present the first stage results of an inverse-docking study which seeks to identify potential direct targets of PRIMA-1. PRIMA-1 is well known for its ability to restore mutant p53's tumor suppressor function, leading to apoptosis in several types of cancer cells. For this reason, we believe that potential direct targets of PRIMA-1 identified
in silico should be experimentally screened for their ability to inhibit cancer cell growth. The highest-ranked human protein of our PRIMA-1 docking results is oxidosqualene cyclase (OSC), which is part of the cholesterol synthetic pathway. The results of two followup experiments which treat OSC as a possible anti-cancer target are promising. We show that both PRIMA-1 and Ro 48-8071, a known potent OSC inhibitor, significantly reduce the viability of BT-474 and T47-D breast cancer cells relative to normal mammary cells. In addition, like PRIMA-1, we find that Ro 48-8071 results in increased binding of p53 to DNA in BT-474 cells (which express mutant p53). For the first time, Ro 48-8071 is shown as a potent agent in killing human breast cancer cells. The potential of OSC as a new target for developing anticancer therapies is worth further investigation.
To study potential targets of Danshensu via dual inverse docking.
PharmMapper and idTarget servers were used as tools, and the results were checked with the molecular docking program autodock vina in ...PyRx 0.8.
The disease-related target HRas was rated top, with a pharmacophore model matching well the molecular features of Danshensu. In addition, docking results indicated that the complex was also matched in terms of structure, H-bonds, and hydrophobicity.
Dual inverse docking indicates that HRas may be a potential anticancer target of Danshensu. This approach can provide useful information for studying pharmacological effects of agents of interest.
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▶ Inverse docking has been applied as an efficient method in target identification. ▶ Five inverse docking schemes were evaluated to find out the most effective approach in multiple ...targets identification. ▶ A target database containing a highly qualified dataset that is composed of 1714 entries from 1594 known drug targets covering 18 biochemical functions was collected as a testing pool for inverse docking. ▶ TarSearch-X is the most effective method in multiple targets identification and validation among these five schemes.
The lack of accurate and efficient methods for target identification has been the bottleneck in drug discovery. In recent years, inverse docking has been applied as an efficient method in target identification, and several specific inverse docking strategies have been employed in academic and industrial researches. However, the effectiveness of these docking strategies in multiple targets identification is unclear. In this study, five inverse docking schemes were evaluated to find out the most effective approach in multiple targets identification. A target database containing a highly qualified dataset that is composed of 1714 entries from 1594 known drug targets covering 18 biochemical functions was collected as a testing pool for inverse docking. The inverse docking engines including GOLD, FlexX, Tarfisdock and two in-house target search schemes TarSearch-X and TarSearch-M were evaluated by eight multiple target systems in the dataset. The results show that TarSearch-X is the most effective method in multiple targets identification and validation among these five schemes, and the effectiveness of GOLD in multiple targets identification is also acceptable. Moreover, these two inverse docking strategies will also be helpful in predicting the undesirable effects of drugs, such as toxicity.
Tanshinone IIA is a pharmacologically active ingredient extracted from Danshen, a Chinese traditional medicine. Its molecular mechanisms are still unclear. The present study utilized computational ...approaches to uncover the potential targets of this compound. In this research, PharmMapper server was used as the inverse docking tool and the results were verified by Autodock vina in PyRx 0.8, and by DRAR-CPI, a server for drug repositioning via the chemical-protein interactome. Results showed that the retinoic acid receptor alpha (RARα), a target protein in acute promyelocytic leukemia (APL), was in the top rank, with a pharmacophore model matching well the molecular features of Tanshinone IIA. Moreover, molecular docking and drug repurposing results showed that the complex was also matched in terms of structure and chemical-protein interactions. These results indicated that RARα may be a potential target of Tanshinone IIA for APL. The study can provide useful information for further biological and biochemical research on natural compounds.
Kinetin, a cytokinin which promotes seed germination by inhibiting the action of abscisic acid, is an important molecule known to trigger various molecular mechanisms by interacting with an array of ...proteins shown from experimental observations in various model organisms. We report here the prediction of most probable protein targets of kinetin from spinach proteome using in silico approaches. Inverse docking and ligand-based similarity search was performed using kinetin as molecule. The former method prioritized six spinach proteins, whereas the latter method provided a list of protein targets retrieved from several model organisms. The most probable protein targets were selected by comparing the rank list of docking and ligand similarity methods. Both of these methods prioritized chitinase as the most probable protein target (Δ
G
pred
= 5.064 kcal/mol) supported by the experimental structure of yeast chitinase 1 complex with kinetin (PDB: 2UY5) and
Gliocladium roseum
chitinase complex with 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (caffeine; 3G6M) which bears a 3D similarity of 0.43 with kinetin. An in vitro study to evaluate the effect of kinetin on spinach seed germination indicated that a very low concentration of kinetin (0.5 mg/l) did not show a significant effect compared to control in inducing seed germination process. Further, higher levels of kinetin (>0.5 mg/l) constituted an antagonist effect on spinach seed germination. It is anticipated that kinetin may have a molecular interaction with prioritized protein targets synthesized during the seed germination process and reduces growth. Thus, it appears that kinetin may not be a suitable hormone for enhancing spinach seed germination in vitro.
While many experimental and clinical studies of traditional Chinese medicine (TCM) have been reported over recent years, the applications of computational methods to drug discovery from Chinese herbs ...are still at an early stage. In the light of the spread of TCM to other parts of the world over the last few decades, and the growing number of publications in languages other than Chinese, this article focuses on work published in English and accessible to an international audience. Sources of information in appropriate format are particularly important for informatics, and the growing number of TCM-related databases is discussed. Applications of virtual screening both to the identification of single and multiple target ligands are covered, as are developments in 'target fishing', a novel technique which seeks to identify multiple receptors to which a compound may bind. Finally, the role of informatics in bridging the gulf between the paradigms of TCM and biomedical science is explored, and a discussion presented as to its use in probing the molecular basis of TCM.
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