Search results for "Molecular Docking"
showing 10 items of 186 documents
A Molecular Dynamics-Shared Pharmacophore Approach to Boost Early-Enrichment Virtual Screening: A Case Study on Peroxisome Proliferator-Activated Rec…
2016
Molecular dynamics (MD) simulations can be used, prior to virtual screening, to add flexibility to proteins and study them in a dynamic way. Furthermore, the use of multiple crystal structures of the same protein containing different co-crystallized ligands can help elucidate the role of the ligand on a protein's active conformation, and then explore the most common interactions between small molecules and the receptor. In this work, we evaluated the contribution of the combined use of MD on crystal structures containing the same protein but different ligands to examine the crucial ligand-protein interactions within the complexes. The study was carried out on peroxisome proliferator-activat…
Chemical Proteomics-Guided Identification of a Novel Biological Target of the Bioactive Neolignan Magnolol
2019
Understanding the recognition process between bioactive natural products and their specific cellular receptors is of key importance in the drug discovery process. In this outline, some potential targets of Magnolol, a natural bioactive compound, have been identified by proteomic approaches. Among them, Importin-β1 has been considered as the most relevant one. A direct binding between Magnolol and this nuclear chaperone has been confirmed by DARTS and molecular docking, while its influence on Importin-β1 translocation has been evaluated by in vitro assays.
A frozen analogue approach to aminopyridinylimidazoles leading to novel and promising p38 MAP kinase inhibitors.
2012
In this study we report the design, synthesis, and biological evaluation of constrained aminopyridinylimidazoles as p38α MAP kinase inhibitors. The frozen analogue approach focused on the pyridinyl unit, using purine bioisosteres as constrained structure analogues. The identification of the most potent bioisostere was followed by a further derivatization to address hydrophobic region II. In combination with C-2 modifications of the imidazole core, we were able to design highly active inhibitors on the p38α MAP kinase. The inhibitor design presented herein represents a promising and highly efficient advancement of recent stages of development in this class of p38 MAP kinase inhibitors. In co…
Design, Synthesis and Biological Evaluation of Novel Pyrazolo[1,2,4]triazolopyrimidine Derivatives as Potential Anticancer Agents
2021
Three novel pyrazolo-[4,3-e][1,2,4]triazolopyrimidine derivatives (1, 2, and 3) were designed, synthesized, and evaluated for their in vitro biological activity. All three compounds exhibited different levels of cytotoxicity against cervical and breast cancer cell lines. However, compound 1 showed the best antiproliferative activity against all tested tumor cell lines, including HCC1937 and HeLa cells, which express high levels of wild-type epidermal growth factor receptor (EGFR). Western blot analyses demonstrated that compound 1 inhibited the activation of EGFR, protein kinase B (Akt), and extracellular signal-regulated kinase (Erk)1/2 in breast and cervical cancer cells at concentrations…
Improving Docking Performance Using Negative Image-Based Rescoring
2018
Despite the large computational costs of molecular docking, the default scoring functions are often unable to recognize the active hits from the inactive molecules in large-scale virtual screening experiments. Thus, even though a correct binding pose might be sampled during the docking, the active compound or its biologically relevant pose is not necessarily given high enough score to arouse the attention. Various rescoring and post-processing approaches have emerged for improving the docking performance. Here, it is shown that the very early enrichment (number of actives scored higher than 1% of the highest ranked decoys) can be improved on average 2.5-fold or even 8.7-fold by comparing th…
Corylus avellana: A Source of Diarylheptanoids With α-Glucosidase Inhibitory Activity Evaluated by in vitro and in silico Studies
2022
Corylus avellana hard shells, green leafy involucres, leaves, and male flowers have shown to be a source of diarylheptanoids, a class of natural products with promising biological activities. Cyclic diarylheptanoids, named giffonins, were isolated from the Italian cultivar “Tonda di Giffoni.” Even if many efforts have been made to establish the chemistry of these compounds, little is known about their biological properties. Herein, the inhibitory effects of diarylheptanoids isolated from C. avellana byproducts against α-glucosidase enzyme were evaluated. Molecular docking experiments disclosed the establishment of several key interactions between all the screened diarylheptanoids and the pr…
Study of the aryl hydrocarbon receptor mediated effects through in silico modeling and in vitro bioassays
2020
The aryl hydrocarbon receptor (AhR) is a cytoplasmatic sensor of diverse endogenous and exogenous substances. In a toxicological context, the former known as “dioxin receptor” has been investigated as a xenobiotic chemoreceptor and due to its roles in mediating carcinogenesis, endocrine disruption, among other immunological, hepatic, cardiovascular, and dermal toxicity mechanisms. The deep physiological implications of AhR in cellular proliferation, adhesion, division, differentiation, as well as in the reproductive, immunological and cardiovascular homeostasis have opened a new field of research in order to harness AhR’s pharmacological potential. Hence, AhR has become a therapeutic target…
A Practical Perspective : The Effect of Ligand Conformers on the Negative Image-Based Screening
2019
Negative image-based (NIB) screening is a rigid molecular docking methodology that can also be employed in docking rescoring. During the NIB screening, a negative image is generated based on the target protein’s ligand-binding cavity by inverting its shape and electrostatics. The resulting NIB model is a drug-like entity or pseudo-ligand that is compared directly against ligand 3D conformers, as is done with a template compound in the ligand-based screening. This cavity-based rigid docking has been demonstrated to work with genuine drug targets in both benchmark testing and drug candidate/lead discovery. Firstly, the study explores in-depth the applicability of different ligand 3D conformer…
Optimizing the SYBR green related cyanine dye structure to aim for brighter nucleic acid visualization
2022
In recent years, the studies of RNA and its use for the development of RNA based vaccines have increased drastically. Although cyanine dyes are commonly used probes for studying nucleic acids, in a wide range of applications, there is still a growing need for better and brighter dyes. To meet this demand, we have systematically studied the structure of SYBR green-related cyanine dyes to gain a deeper understanding of their interactions with biomolecules especially how they interact with nucleic acids and the structural components which makes them strongly fluorescent. Herein, five new dyes were synthesized, and their photophysical properties were evaluated. Observations of photophysical cha…
Synthesis and biological evaluation of sphingosine kinase 2 inhibitors with anti-inflammatory activity.
2019
The synthesis of inhibitors of SphK2 with novel structural scaffolds is reported. These compounds were designed from a molecular modeling study, in which the molecular interactions stabilizing the different complexes were taken into account. Particularly interesting is that 7‐bromo‐2‐(2‐phenylethyl)‐2,3,4,5‐tetrahydro‐1,4‐epoxynaphtho[1,2‐b]azepine, which is a selective inhibitor of SphK2, does not exert any cytotoxic effects and has a potent anti‐inflammatory effect. It was found to inhibit mononuclear cell adhesion to the dysfunctional endothelium with minimal impact on neutrophil–endothelial cell interactions. The information obtained from our theoretical and experimental study can be us…