1,721,063 research outputs found
The in silico fischer lock-and-key model: The combined use of molecular descriptors and docking poses for the repurposing of old drugs
Full text linkNot always lead compound and/or derivatives are suitable for the specific biological target for which they are designed but, in some cases, discarded compounds proved to be good binders for other biological targets; therefore, drug repurposing constitute a valid alternative to avoid waste of human and financial resources. Our virtual lock-and-key methods, VLKA and Conf-VLKA, furnish a strong support to predict the efficacy of a designed drug a priori its biological evaluation, or the correct biological target for a set of the selected compounds, allowing thus the repurposing of known and unknown, active and inactive compounds
Molecular modelling studies on dopamine-amino acid conjugates as potential dopaminergic modulators
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TOWARD ENRICHED VHTS FOR CDK2 INHIBITORS: MOLECULAR DYNAMICS, PHARMACOPHORE MODELLING, AND DOCKING
Full text linkCyclin-Dependent Kinases-2 (CDK2) are members of the serine/threonine protein kinases family. They play an important role in the regulation events of the eukaryotic cell division cycle, especially during the G1 to S phase transition. Experimental evidence indicates that excessive expression of CDK2s should cause abnormal cell cycle regulation. Therefore, since a long time, CDK2s have been considered potential therapeutic targets for cancer therapy. In this work, we collected one-hundred and forty-nine complexes of inhibitors bound in the CDK2-ATP pocket submitting to short MD simulations (10ns) and free energy calculation by means of MM-GBSA. The calculate ∆G values have been compared with experimental data (Ki, Kd, and IC50). Information collected on short MD simulations of protein-ligand complexes has been used to perform molecular modeling approaches that incorporates flexibility into structure-based pharmacophore modeling (Common Hits Approach, CHA,1 and Molecular dYnamics SHAred PharmacophorE, MYSHAPE2 approach) and constraints docking, to enrich the hits list of virtual screening. Short simulations proved to be exhaustive to examine the crucial ligand-protein interactions within the complexes
Unveiling Novel Hybrids Quinazoline/Phenylsulfonylfuroxan Derivatives with Potent Multi-Anticancer Inhibition: DFT and In Silico Approach Combining 2D-QSAR, Molecular Docking, Dynamics Simulations, and ADMET Properties
No full textIn this work, the biological activities of 29 novel quinazoline/phenylsulfonylfuroxan derivatives (1a–z, 1aa, 1ab, 2a, 2b, 2d, and 2f) were computationally investigated as potential anti-cancer inhibitors against five cell lines, i.e., H1975, MCF-7, Eca-109, MGC-803, and A549, which are involved in various diseases, including lung, breast, esophageal squamous carcinoma, and gastric cancer. The 2D-QSAR predictive approach, exploiting multiple linear regression (MLR) models and rigorous internal and external cross-validation, showed a correlation factor R2 of range: 0.68−0.82. Moreover, the MLR-derived R2test and Y randomization (R2rand) values for the five cell lines are higher than 0.60 and less than 0.3, respectively, indicating a strong alignment with the internal and external validation data. New 70 quinazoline hybrids based on the most effective in vivo 1q inhibitor were designed, and their pIC50 activity was predicted. The best-scoring 15 (N1–N15) compounds were further evaluated using molecular docking and dynamics simulations (100 ns) with the VEGFR-2 kinase target (PDB code: 3U6J). All the data sets accurately predict the strongest binding affinity for the selected (N6, N7, N9, and N11) molecules, as evidenced by the highest docking score, hydrogen bond energy, and significant amino acid steric interactions. Furthermore, the RMS/RMSF/Rg dynamics parameters show that the formed complexes are satisfactorily stable. The ADMET properties indicate that the selected new ligands have shown a promising drug-like profile and can be considered potential candidates for future anti-cancer therapies, with perspective validating their anticancer activity by in vitro and in vivo studies
The Molecular dYnamics SHAred PharmacophorE (MYSHAPE) approacha new tool to arise docking and pharmacophore modeling performance: virtues and vices
No full textIn a recent paper, we presented a new virtual screening workflow that addresses the arising issues of molecular docking and pharmacophore modeling when using a single set of coordinates and a single active ligand [1]. MD simulations were carried out and ligand-protein interactions were analyzed and collected together with their appearance frequency. A pharmacophore model was then created using only the common feature patterns that all the ligands exhibited during MD simulations. This ‘Molecular dYnamics SHAred PharmacophorE’ was then used for virtual screening on active and inactive molecules library. MYSHAPE was also used as constraints for the creation of the docking grid. The application of the MYSHAPE model showed an interesting increase of the screening capability both in terms of sensitivity of the model and specificity when compared to the PDB models. This work [1] was a first essay for a workflow that should be applied to different proteins. In the present study we tried to apply the MYSHAPE approach to other three different ligand-protein systems (ERα; RXRα, and MAPKp38) with the aim to optimize the method to each different biological target taking in consideration the early recognition. The obtained results for these new targets confirmed that it is mandatory, to optimize the virtual screening campaign, the selection of dynamic features and constraints for docking. In particular, the addition of the constraints derived from MD simulation leads to an improvement in the model selectivity for RXRα and ERα in standard precision docking mode. For MAPKp38, validation metrics such as ROC, BEDROC, and AUAC are higher in extra precision mode. For the pharmacophore modeling, the addition of the features derived from the common interactions in MD simulations guarantee an improvement in the AUC for RXRα (37%), and ERα (77%), but light improvement for MAPKp38. MD simulation derived common interactions revealed fundamental for docking selectivity, while they are applied to pharmacophore modeling only when the number of final features in the common and dynamic pharmacophore is higher than the starting static pharmacophore. The strength behind the protocol is the ease of use related to the improvement of results. It also could represent a valid alternative to use very time-consuming techniques such as XP docking with constraints.
Reference: 1. Perricone, U., Wieder, M., Seidel, T., Langer, T., Padova, A., Almerico, A. M., & Tutone, M. (2017). A Molecular Dynamics–Shared Pharmacophore Approach to Boost Early-Enrichment Virtual Screening: A Case Study on Peroxisome Proliferator-Activated Receptor α. ChemMedChem, 2017. DOI: 10.1002/cmdc.20160052
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Comparing molecular dynamics-derived pharmacophore models with docking: A study on CDK-2 inhibitors
No full textWe compared the performance of molecular dynamics (MD)-derived pharmacophore modeling approaches, Common Hit Approach (CHA), and the Molecular dYnamics SHAred PharmacophorE (MYSHAPE) approach, with semi-flexible constrained/unconstrained docking. The aim of this work is to enrich the hit-list of a virtual screening on CDK-2 known inhibitors as a case study. Cyclin-dependent kinases (CDKs) deregulation is associated with cancer growth. CDKs are an attractive target for anticancer agents. MD-derived pharmacophore models have been obtained with LigandScout 4.2.1. Docking analysis has been performed through Glide 7.6. The results highlighted the MYSHAPE approach has a better performance when multiple target-ligand complexes are available (ROC5% = 0.99). Moreover, the use of short molecular dynamics simulations improves the performance of the screening (ROC5% = 0.98–0.99) with respect to docking (ROC5% = 0.89–0.94). Outcomes of this work indicate that these approaches are highly suitable for prospective screening by a non-expert, and could be useful for the identification of novel CDK-2 inhibitors
Investigation on quantitative structure-activity relationships of 1,3,4-oxadiazole derivatives as potential telomerase inhibitors
Full text linkBackground: Telomerase, a reverse transcriptase, maintains telomere and chromosomes integrity of dividing cells, while it is inactivated in most somatic cells. In tumor cells, telomerase is highly activated, and works in order to maintain the length of telomeres causing immortality, hence it could be considered as a potential marker to tumorigenesis.A series of 1,3,4-oxadiazole derivatives showed significant broad-spectrum anticancer activity against different cell lines, and demonstrated telomerase inhibition. Methods: This series of 24 N-benzylidene-2-((5-(pyridine-4-yl)-1,3,4-oxadiazol-2yl)thio)acetohydra-zide derivatives as telomerase inhibitors has been considered to carry out QSAR studies. The endpoint to build QSAR models is determined by the IC50 values for telomerase inhibition, i.e., the concentration (μM) of inhibitor that produces 50% inhibition. These values were converted to pIC50 (-log IC50) values. We used the most common and transparent method, where models are described by clearly expressed mathematical equations: Multiple Linear Regression (MLR) by Ordinary Least Squares (OLS). Results: Validated models with high correlation coefficients were developed. The Multiple Linear Regression (MLR) models, by Ordinary Least Squares (OLS), showed good robustness and predictive capability, according to the Multi-Criteria Decision Making (MCDM = 0.8352), a technique that simultaneously enhances the performances of a certain number of criteria. The descriptors selected for the models, such as electrotopological state (E-state) descriptors, and extended topochemical atom (ETA) descriptors, showed the relevant chemical information contributing to the activity of these compounds. Conclusion: The results obtained in this study make sure about the identification of potential hits as prospective telomerase inhibitors
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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