Echinococcosis is an important parasitic disease that threats human health and animal husbandry worldwide. However, the low cure rate of clinical drugs for this disease is a challenge. Hence, novel ...compounds and specific drug targets are urgently needed. In this study, we identified drug targets of amino alcohols with effects on
species. The drug targets were predicted with the idTarget web server. Corresponding three-dimensional structures of the drug targets were built after sequence BLAST analysis and homology modeling. After further screening by molecular docking, the activities of the candidate targets were validated
. We ultimately identified glycogen phosphorylase as a potential drug target for amino alcohols. There are two genes coding glycogen phosphorylase in
(EgGp1 and EgGp2). EgGp1 was abundant in
PSCs, while EgGp2 was abundant in the cysts. These proteins were located at suckers and somas of
PSCs and near the rostellum of cysts developed from PSCs. The effective compounds docked into a pocket consisting of E124, K543 and K654 and affected (either inhibited or enhanced) the activity of
glycogen phosphorylase. In this study, we designed a method to predict drug targets for echinococcosis treatment based on inverse docking. The candidate targets found by this method can contribute not only to understanding of the modes of action of amino alcohols but also to modeling-aided drug design based on targets.
Organophosphate esters (OPEs) have gained considerable interest from many environmental chemists and toxicologists due to their frequent detection in the environment and potential adverse effects on ...health. Nuclear hormone receptors (NHRs) were found to mediate many of their adverse effects. However, our knowledge regarding the direct binding and interaction between OPEs and NHRs is limited. In this study, Endocrine Disruptome, an online computational tool based on the technique of inverse docking, was used to calculate the binding affinity score of 25 individual OPEs with 12 different human NHRs. Results showed that 20% of potential binding interactions between the OPEs and NHRs had medium-to-high probabilities. The accuracy, sensitivity and specificity of the predictions were 78.8, 60.0 and 80.9%, respectively. OPEs with a benzene ring were more active than those without, among which, tri-o-tolyl phosphate and tri-m-tolyl phosphate displayed the highest activities, suggesting that they might pose the greatest potential risks for interference with endocrine functions. In addition, the antagonistic conformations of androgen receptor and estrogen receptor β were found to be the two most vulnerable NHR conformations. Our findings can further the understanding about the health risk(s) of OPEs.
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•Evaluated potential binding interactions between 25 widely used OPEs and 12 NHRs.•OPEs with a benzene ring were more active than those without.•ARan and ERβan were the two most vulnerable NHR conformations.
Trypanosomiasis is a protozoan disease transmitted via Trypanosoma brucei. This study aimed to examine the metabolic profile and anti-trypanosomal effect of methanol extract of Thunbergia grandifolia ...leaves. The liquid chromatography-high resolution electrospray ionisation mass spectrometry (LC-HRESIMS) revealed the identification of fifteen compounds of iridoid, flavonoid, lignan, phenolic acid, and alkaloid classes. The extract displayed a promising inhibitory activity against T. brucei TC 221 with MIC value of 1.90 μg/mL within 72 h. A subsequent in silico analysis of the dereplicated compounds (i.e. inverse docking, molecular dynamic simulation, and absolute binding free energy) suggested both rhodesain and farnesyl diphosphate synthase as probable targets for two compounds among those dereplicated ones in the plant extract (i.e. diphyllin and avacennone B). The absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling of diphyllin and avacennone were calculated accordingly, where both compounds showed acceptable drug-like properties. This study highlighted the antiparasitic potential of T. grandifolia leaves.
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•New series of pyrazines were designed and synthesized as potential anti-TB agents.•Six compounds displayed potent activity with MIC values ≤6.25 µg/ml.•The most active compounds ...showed reasonable safety margins with SI ≥200.•3-step target fishing study postulated pantothenate synthetase as possible target.•Docking studies on the enzyme highlighted favorable interaction patterns.•Physicochemical, ADME and drug-like properties were found to be adequate.
TB continues to be a leading health threat despite the availability of powerful anti-TB drugs. We report herein the design and synthesis of various hybrid molecules comprising pyrazine scaffold and various formerly identified anti-mycobacterial moieties. Thirty-one compounds were screened in vitro for their activity against Mycobacterium tuberculosis H37Rv strain using MABA assay. The results revealed that six compounds (8a, 8b, 8c, 8d, 14b and 18) displayed significant activity against Mtb with MIC values ≤6.25 µg/ml versus 6.25 µg/ml for pyrazinamide. The most active compounds were then assessed for their in vitro cytotoxicity against PBMC normal cell line using MTT assay and showed SI > 200. Several in silico studies have been carried out for target fishing of the novel compounds such as shape-based similarity, pharmacophore mapping and inverse docking. Based on this multi-step target fishing study, we suggest that pantothenate synthetase could be the possible target responsible for the action of these compounds. The most active compounds were then successfully docked into the active site of pantothenate synthetase enzyme with favorable binding interactions. In addition, in silico prediction of physicochemical, ADMET and drug-like properties were also determined indicating that compounds 8b, 8c and 8d are promising candidates for the development of new anti-TB agents with enhanced activity and better safety profile.
Severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2 is a virus that belongs to the
family. This group of viruses commonly causes colds but possesses a tremendous pathogenic potential. In ...humans, an outbreak of SARS caused by the SARS-CoV virus was first reported in 2003, followed by 2012 when the Middle East respiratory syndrome coronavirus (MERS-CoV) led to an outbreak of Middle East respiratory syndrome (MERS). Moreover, COVID-19 represents a serious socioeconomic and global health problem that has already claimed more than four million lives. To date, there are only a handful of therapeutic options to combat this disease, and only a single direct-acting antiviral, the conditionally approved remdesivir. Since there is an urgent need for active drugs against SARS-CoV-2, the strategy of drug repurposing represents one of the fastest ways to achieve this goal. An
drug repurposing study using two methods was conducted. A structure-based virtual screening of the FDA-approved drug database on SARS-CoV-2 main protease was performed, and the 11 highest-scoring compounds with known 3CL
activity were identified while the methodology was used to report further 11 potential and completely novel 3CL
inhibitors. Then, inverse molecular docking was performed on the entire viral protein database as well as on the
family protein subset to examine the hit compounds in detail. Instead of target fishing, inverse docking fingerprints were generated for each hit compound as well as for the five most frequently reported and direct-acting repurposed drugs that served as controls. In this way, the target-hitting space was examined and compared and we can support the further biological evaluation of all 11 newly reported hits on SARS-CoV-2 3CL
as well as recommend further in-depth studies on antihelminthic class member compounds. The authors acknowledge the general usefulness of this approach for a full-fledged inverse docking fingerprint screening in the future.
Drug repurposing offers a promising alternative to dramatically shorten the process of traditional de novo development of a drug. These efforts leverage the fact that a single molecule can act on ...multiple targets and could be beneficial to indications where the additional targets are relevant. Hence, extensive research efforts have been directed toward developing drug based computational approaches. However, many drug based approaches are known to incur low successful rates, due to incomplete modeling of drug-target interactions. There are also many technical limitations to transform theoretical computational models into practical use. Drug based approaches may, thus, still face challenges for drug repurposing task. Upon this challenge, we developed a consensus inverse docking (CID) workflow, which has a ~ 10% enhancement in success rate compared with current best method. Besides, an easily accessible web server named auto in silico consensus inverse docking (ACID) was designed based on this workflow (
http://chemyang.ccnu.edu.cn/ccb/server/ACID
).
Molecular docking is commonly used for identification of drug candidates targeting a specified protein of known structure. With the increasing emphasis on drug repurposing over recent decades, ...molecular inverse docking has been widely applied to prediction of the potential protein targets of a specified molecule. In practice, inverse docking has many advantages, including early supervision of drugs' side effects and toxicity. MDock developed from our laboratory is a protein-ligand docking software based on a knowledge-based scoring function and has numerous applications to lead identification. In addition to its computational efficiency on ensemble docking for multiple protein conformations, MDock is well suited for inverse docking. In this chapter, we focus on introducing the protocol of inverse docking with MDock. For academic users, the MDock package is freely available at http://zoulab.dalton.missouri.edu/mdock.htm .
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•A steroids-specific target library was constructed and was manually prepared.•The library enriches the potential targets of steroids out of target space.•Ranking by name instead of ...PDB ID makes target screening more efficiency and precise.•Protein flexibility was considered partially leading to more accurate prediction.
Steroids exist universally and play critical roles in various biological processes. Identifying potential targets of steroids is of great significance in studying their physiological and biochemical activities, the side effects and for drug repurposing. Herein, aiming at more precise steroids targets prediction, a steroids-specific target library integrating 3325 PDB or homology modeling structures categorized into 196 proteins was built by considering chemical similarity from DrugBank and biological processes from KEGG. The main properties of this library include: (1) It was manually prepared and checked to eliminate mistakes. (2) The library enriched the possible steroids targets and could decrease the false positives of structure-based target screening for steroids. (3) The ranking by protein name instead of PDB ID could make the screening more efficiency and precise. (4) Protein flexibility was taken into account partially by the different active conformations through the structural redundancy of each category of protein, which leads to more accurate prediction. The case studies of glycocholic acid and 24-epibrassinolide proved its powerful predictive accuracy. In summary, our strategy to build the steroids-specific protein library for steroids target prediction is a promising approach and it provides a novel idea for the target prediction of small molecules.
Various reports have shown Cassiarin alkaloids, selective in vitro activities against various strains of Plasmodium falciparum with low cytotoxicity, which indicates their possible candidature as ...antimalarial drug. However, poor recognition of their protein targets and molecular binding behaviour, certainly limits their exploration as antimalarial drug candidature. To address this, we utilises inverse screening, based on three different docking methodologies in order to find their most putative protein targets. In our study, we screened 1047 protein structures from protein data bank, which belongs to 147 different proteins. Our investigation identified 16 protein targets for Cassiarins. In few cases of identified protein targets, the binding site was poorly studied, which encouraged us to perform comparative sequence and structural studies with their homologous proteins, like as in case of Kelch motif associated protein, Armadillo repeats only protein and Methionine aminopeptidase 1b. In our study, we also found Tryptophanyl-tRNA synthetase and 1-Deoxy-D-Xylose-5-phosphate reductoisomerase proteins are the most common targets for Cassiarins.
Radiation resistance of nasopharyngeal carcinoma (NPC) is a joint effect caused by complex molecular mechanisms. The development of multi-target radiotherapy sensitization agents offered a promising ...method for the treatment of NPC. In this work, the probability of Rhein to be a multi-target radiotherapy sensitization agent was explored through computer aid virtual screening by inverse docking study. In order to validate the accuracy of the computational results, radiotherapy sensitization of Rhein to NPC cells and its effects on the expression of target proteins were evaluated separately by CCK8 assay and Western blotting analysis. Our result demonstrated that Rhein possessed strong binding affinity with RAC1 and HSP90. No cytotoxic concentration of Rhein had radiosensitization effect on nasopharyngeal carcinoma CNE1 cells. After treatment with Rhein and 2Gy radiation, the expression of RAC1 upregulated and the expression of HSP90 down-regulated in cells. Based on the above data, Rhein is likely to become an attractive lead compound for the future design of multi-target radiotherapy sensitization agents.
In this work, the probability of Rhein to be a multi-target radiotherapy sensitization agent was explored through computer aid virtual screening by inverse docking study and biological activity determination. Computational and experimental results indicated that radiotherapy sensitization mediated by Rhein was probably not by effecting on one single target, but simultaneously by targeting the node proteins of RAC1, EGFR and HSP90, which implied that these proteins may be the checkpoint targets of NPC CNE1 cells in the radiotherapy process, it also suggested that Rhein was a promising multi-target agent in regulating the sensitivity of NPC CNE1 cells to radiation. More importantly, this research provided a tactics for design of multi-targeted radiotherapy sensitization agents. Display omitted
•Inverse docking was able to identify multi-radiosensitization targets of Rhein.•Rhein had radiosensitization activity for nasopharyngeal carcinoma CNE1 cells.•In-silico and in vitro data found Rhein as a multi-targets radiosensitization agent.
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