Search results for " docking"
showing 10 items of 226 documents
New potent antibacterials against Gram-positive multiresistant pathogens: effects of side chain modification and chirality in linezolid-like 1,2,4-ox…
2014
The effects of side chain modification and chirality in linezolid-like 1,2,4-oxadiazoles have been studied to design new potent antibacterials against Gram-positive multidrug-resistant pathogens. The adopted strategy involved a molecular modelling approach, the synthesis and biological evaluation of new designed compounds, enantiomers separation and absolute configuration assignment. Experimental determination of the antibacterial activity of the designed (S)-1-((3-(4-(3-methyl-1,2,4-oxadiazol-5- yl)phenyl)-oxazolidin-2-one-5-yl)methyl)-3-methylthiourea and (S)-1-((3-(3-fluoro-4-(3-methyl-1,2,4- oxadiazol-5-yl)phenyl)-oxazolidin-2-one-5-yl)methyl)-3-methylthiourea against multidrug resistan…
The crystal structure of a 250-kDa heterotetrameric particle explains inhibition of sheddase meprin β by endogenous fetuin-B
2021
Meprin β (Mβ) is a multidomain type-I membrane metallopeptidase that sheds membrane-anchored substrates, releasing their soluble forms. Fetuin-B (FB) is its only known endogenous protein inhibitor. Herein, we analyzed the interaction between the ectodomain of Mβ (MβΔC) and FB, which stabilizes the enzyme and inhibits it with subnanomolar affinity. The MβΔC:FB crystal structure reveals a ∼250-kDa, ∼160-Å polyglycosylated heterotetrameric particle with a remarkable glycan structure. Two FB moieties insert like wedges through a “CPDCP trunk” and two hairpins into the respective peptidase catalytic domains, blocking the catalytic zinc ions through an “aspartate switch” mechanism. Uniquely, the …
Deciphering the Potential of Pre and Pro-Vitamin D of Mushrooms against Mpro and PLpro Proteases of COVID-19: An In Silico Approach
2022
Vitamin D’s role in combating the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the virus causing COVID-19, has been established in unveiling viable inhibitors of COVID-19. The current study investigated the role of pre and pro-vitamin D bioactives from edible mushrooms against Mpro and PLpro proteases of SARS-CoV-2 by computational experiments. The bioactives of mushrooms, specifically ergosterol (provitamin D2), 7-dehydrocholesterol (provitamin-D3), 22,23-dihydroergocalciferol (provitamin-D4), cholecalciferol (vitamin-D3), and ergocalciferol (vitamin D2) were screened against Mpro and PLpro. Molecular docking analyses of the generated bioactive protease complexes unr…
Design and Synthesis of Novel 1,3-Thiazole and 2-Hydrazinyl-1,3-Thiazole Derivatives as Anti-Candida Agents: In Vitro Antifungal Screening, Molecular…
2019
In the context of there being a limited number of clinically approved drugs for the treatment of Candida sp.-based infections, along with the rapid development of resistance to the existing antifungals, two novel series of 4-phenyl-1,3-thiazole and 2-hydrazinyl-4-phenyl-1,3-thiazole derivatives were synthesized and tested in vitro for their anti-Candida potential. Two compounds (7a and 7e) showed promising inhibitory activity against the pathogenic C. albicans strain, exhibiting substantially lower MIC values (7.81 &mu
Evaluation of the IKKβ Binding of Indicaxanthin by Induced-Fit Docking, Binding Pose Metadynamics, and Molecular Dynamics
2021
Background: Indicaxanthin, a betaxanthin belonging to the betalain class of compounds, has been recently demonstrated to exert significant antiproliferative effects inducing apoptosis of human melanoma cells through the inhibition of NF-κB as the predominant pathway. Specifically, Indicaxanthin inhibited IκBα degradation in A375 cells. In resting cells, NF-κB is arrested in the cytoplasm by binding to its inhibitor protein IκBα. Upon stimulation, IκBα is phosphorylated by the IKK complex, and degraded by the proteasome, liberating free NF-κB into the nucleus to initiate target gene transcription. Inhibition of the IKK complex leads to the arrest of the NF-κB pathway.Methods: To acquire deta…
Fragment- and negative image-based screening of phosphodiesterase 10A inhibitors.
2019
A novel virtual screening methodology called fragment- and negative image-based (F-NiB) screening is introduced and tested experimentally using phosphodiesterase 10A (PDE10A) as a case study. Potent PDE10A-specific small-molecule inhibitors are actively sought after for their antipsychotic and neuroprotective effects. The F-NiB combines features from both fragment-based drug discovery and negative image-based (NIB) screening methodologies to facilitate rational drug discovery. The selected structural parts of protein-bound ligand(s) are seamlessly combined with the negative image of the target's ligand-binding cavity. This cavity- and fragment-based hybrid model, namely its shape and electr…
A MULTI-LEVEL FUNCTIONAL STUDY OF A SNAP25 AT-RISK VARIANT FOR BIPOLAR DISORDER AND SCHIZOPHRENIA
2019
Background The synaptosomal associated protein SNAP25 is crucial for synaptic vesicle docking and fusion and has been associated with multiple psychiatric conditions. We recently identified a promoter variant in SNAP25, rs6039769, associated with bipolar disorder and gene expression in prefrontal cortex. Methods Here, we performed a genetic association study using this variation on two independent cohorts of 288 and 173 subjects with schizophrenia and 315 unaffected control individuals. We replicated our results using data from the schizophrenia group of the Psychiatric Genomics Consortium (PGC). Functional consequences combined both in vitro and post-mortem gene expression analysis on 30 p…
Cytotoxicity and antimitotic activity of Rhinella schneideri and Rhinella marina venoms.
2019
Abstract Ethnopharmacological relevance Rhinella schneideri and Rhinella marina are toad venoms distributed in different parts of the world, including Brazil, Columbia and amazon. Venoms extracted from different species have many clinical applications such as antimicrobial cardiotonics and treatment of cancer. Aim of the study; In this study, we aim to investigate the effect of venoms extracted from R. schneideri and R. marina on cancer cells and verify possible mechanism of action. Material and method Cytotoxicity analyses was performed using the resazurin reduction assay, where different concentrations of venoms were tested against sensitive CCRF-CEM and P-gp overexpressing ADR/CEM5000 le…
Molecular mechanisms of rosmarinic acid from Salvia miltiorrhiza in acute lymphoblastic leukemia cells
2015
Abstract Ethnopharmacological relevance Rosmarinic acid (RA), a major hydrosoluble bioactive compound found in the Chinese medicinal herb, Salvia miltiorrhiza Bunge, which has been used in traditional Chinese medicine to treat various diseases, including cancer. However, the mechanisms have not been fully elucidated. Aim of the study Guided by microarray hybridization and Ingenuity Pathway Analysis, we identified modes of action of rosmarinic acid (RA) isolated from S. miltiorrhiza on acute lymphoblastic leukemia cells. Materials and methods Microarray data were verified by independent methods: Real-time RT-PCR (mRNA expression), resazurin assay (cytotoxicity of RA towards parental CCRF-CEM…
Proline-Based Allosteric Inhibitors of Zika and Dengue Virus NS2B/NS3 Proteases
2019
The NS2B/NS3 serine proteases of the Zika and Dengue flaviviruses are attractive targets for the development of antiviral drugs. We report the synthesis and evaluation of a new, proline-based compound class that displays allosteric inhibition of both proteases. The structural features relevant for protease binding and inhibition were determined to establish them as new lead compounds for flaviviral inhibitors. Based on our structure-activity relationship studies, the molecules were further optimized, leading to inhibitors with submicromolar IC50 values and improved lipophilic ligand efficiency. The allosteric binding site in the proteases was probed using mutagenesis and covalent modificati…