Mechanistic Insight on the Mode of Action of Colletoic Acid.
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ABSTRACT:
SUBMITTER: Ling T
PROVIDER: S-EPMC8688139 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundDevelopment of a cancerous cell takes place when it ceases to respond to growth-inhibiting signals and multiplies uncontrollably and can detach and move to other parts of the body; the process called as metastasis. A particular set of cysteine proteases are very active during cancer metastasis, Cathepsins being one of them. They are involved in tumor growth and malignancy and have also been reported to be overexpressed in tumor cell lines. In the present study, a combinatorial approach comprising three-dimensional quantitative structure-activity relationship (3D QSAR), ligand-based pharmacophore modelling and search followed by cathepsin L structure-based high throughput screening was carried out using an initial set of 28 congeneric thiosemicarbazone derivatives as cathepsin L inhibitors. A 3D QSAR was derived using the alignment of a common thiosemicarbazone substructure. Essential structural features responsible for biological activity were taken into account for development of a pharmacophore model based on 29 congeneric thiosemicarbazone derivatives. This model was used to carry out an exhaustive search on a large dataset of natural compounds. A further cathepsin L structure-based screen identified two top scoring compounds as potent anti-cancer leads.ResultsThe generated 3D QSAR model showed statistically significant results with an r(2) value of 0.8267, cross-validated correlation coefficient q(2) of 0.7232, and a pred_r(2) (r(2) value for test set) of 0.7460. Apart from these, a high F test value of 30.2078 suggested low probability of the model's failure. The pharmacophoric hypothesis chosen for searching the natural compound libraries was identified as DDHRR, where two Ds denote 2 hydrogen donors, H represents a hydrophobic group and two Rs represent aromatic rings, all of which are essential for the biological activity. We report two potential drug leads ZINC08764437 (NFP) and ZINC03846634 (APQ) obtained after a combined approach of pharmacophore-based search and structure-based virtual screen. These two compounds displayed extra precision docking scores of -7.972908 and -7.575686 respectively suggesting considerable binding affinity for cathepsin L. High activity values of 5.72 and 5.75 predicted using the 3D QSAR model further substantiated the inhibitory potential of these identified leads.ConclusionThe present study attempts to correlate the structural features of thiosemicarbazone group with their biological activity by development of a robust 3D QSAR model. Being statistically valid, this model provides near accurate values of the activities predicted for the congeneric set on which it is based. These predicted activities are good for the test set compounds making it indeed a statistically sound 3D QSAR model. The identified pharmacophore model DDHRR.8 comprised of all the essential features required to interact with the catalytic triad of cathepsin L. A search for natural compounds based on this pharmacophore followed by docking studies further screened out two top scoring candidates: NFP and AFQ. The high binding affinity and presence of essential structural features in these two compounds make them ideal for consideration as natural anti-tumoral agents. Activity prediction using 3D QSAR model further validated their potential as worthy drug candidates against cathepsin L for treatment of cancer.
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Project description:Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most prevalent known cause of autosomal dominant Parkinson's disease. The LRRK2 gene encodes a Roco protein featuring a Ras of complex proteins (ROC) GTPase and a kinase domain linked by the C-terminal of ROC (COR) domain. Here, we explored the effects of the Y1699C pathogenic LRRK2 mutation in the COR domain on GTPase activity and interactions within the catalytic core of LRRK2. We observed a decrease in GTPase activity for LRRK2 Y1699C comparable to the decrease observed for the R1441C pathogenic mutant and the T1348N dysfunctional mutant. To study the underlying mechanism, we explored the dimerization in the catalytic core of LRRK2. ROC-COR dimerization was significantly weakened by the Y1699C or R1441C/G mutation. Using a competition assay, we demonstrated that the intra-molecular ROC : COR interaction is favoured over ROC : ROC dimerization. Interestingly, the intra-molecular ROC : COR interaction was strengthened by the Y1699C mutation. This is supported by a 3D homology model of the ROC-COR tandem of LRRK2, showing that Y1699 is positioned at the intra-molecular ROC : COR interface. In conclusion, our data provides mechanistic insight into the mode of action of the Y1699C LRRK2 mutant: the Y1699C substitution, situated at the intra-molecular ROC : COR interface, strengthens the intra-molecular ROC : COR interaction, thereby locally weakening the dimerization of LRRK2 at the ROC-COR tandem domain resulting in decreased GTPase activity.
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Project description:Production of Shiga toxins by enterohemorrhagic Escherichia coli (EHEC) which is responsible for the pathogenicity of these strains, is strictly correlated with induction of lambdoid bacteriophages present in the host's genome, replication of phage DNA and expression of stx genes. Antibiotic treatment of EHEC infection may lead to induction of prophage into a lytic development, thus increasing the risk of severe complications. This, together with the spread of multi-drug resistance, increases the need for novel antimicrobial agents. We report here that isothiocyanates (ITC), plant secondary metabolites, such as sulforaphane (SFN), allyl isothiocyanate (AITC), benzyl isothiocynanate (BITC), phenyl isothiocyanate (PITC) and isopropyl isothiocyanate (IPRITC), inhibit bacterial growth and lytic development of stx-harboring prophages. The mechanism underlying the antimicrobial effect of ITCs involves the induction of global bacterial stress regulatory system, the stringent response. Its alarmone, guanosine penta/tetraphosphate ((p)ppGpp) affects major cellular processes, including nucleic acids synthesis, which leads to the efficient inhibition of both, prophage induction and toxin synthesis, abolishing in this way EHEC virulence for human and simian cells. Thus, ITCs could be considered as potential therapeutic agents in EHEC infections.
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2013-05-13 | E-ERAD-135 | biostudies-arrayexpress
Project description:Herbicides that mimic the natural auxin indole-3-acetic acid are widely used in weed control. One common auxin-like herbicide is dicamba, but despite its wide use, plant gene responses to dicamba have never been extensively studied. To further understand dicamba's mode of action, we utilized Arabidopsis auxin-insensitive mutants and compared their sensitivity to dicamba and the widely-studied auxinic herbicide 2,4-dichlorophenoxyacetic acid (2,4-D). The mutant axr4-2, which has disrupted auxin transport into cells, was resistant to 2,4-D but susceptible to dicamba. By comparing dicamba resistance in auxin signalling F-box receptor mutants (tir1-1, afb1, afb2, afb3, and afb5), only tir1-1 and afb5 were resistant to dicamba, and this resistance was additive in the double tir1-1/afb5 mutant. Interestingly, tir1-1 but not afb5 was resistant to 2,4-D. Whole genome analysis of dicamba-induced gene expression showed that 10 hours after application, dicamba stimulated many stress-responsive and signalling genes, including those involved in biosynthesis or signalling of auxin, ethylene, and abscisic acid (ABA), with TIR1 and AFB5 required for the dicamba-responsiveness of some genes. Research into dicamba-regulated gene expression and the selectivity of auxin receptors has provided molecular insight into dicamba-regulated signalling and could help in the development of novel herbicide resistance in crop plants.
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