176,851 research outputs found
In vitro and in silico studies of polycondensed diazine systems as anti-infective agents
No full textInfective diseases caused by protozoarian agents are still relevant today
more than ever. In fact, they represent the first cause of death all over the world
with seventeen millions victims every year. The development of drug resistance
and the broad diffusion of these pathologies make actual the research of new
molecules able to act as selective and effective anti-infective chemotherapics.[1]
Recently several polycondensed
diazine derivatives, by means 1,3-dipolar
cycloaddition, reactions [2, 3] were
synthesized.
A broad selection of these
compounds chosen with a wide pattern of
substitutions were submitted to biological
in vitro screening against Plasmodium
falciparum, Leishmania Infantum,
Trypanosoma brucei e Trypanosoma
cruzi, and they resulted active at
micromolar level. In order to identify
molecular targets able to explain the
mechanism of action of these compounds,
we performed Induced Fit Docking/MM-GBSA modeling studies. The obtained
results give interesting indications about the probable mechanism of action of the
most active compounds.
[1] M. Gonzaalez, H. Cerecetto, Expert Opinion on Therapeutic Patents, 21,
2011, 699-715.
[2] A. Lauria, A. Guarcello, G. Dattolo, A.M. Almerico, Tetrahedron Lett., 49,
2008, 1847-1850.
[3] A. Lauria, A. Guarcello, G. Macaluso, G. Dattolo, A.M. Almerico,
Tetrahedron Lett., 50, 2009, 7333-7336
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
Manuale di chimica farmaceutica. Progettazione, meccanismo d'azione e metabolismo dei farmaci
No full textConsensus modelling and molecular dynamics studies for the identification of novel telomerase inhibitors as anti-cancer agents
No full textTelomerase plays an important role in early stages of life-maintaing telomere and chromosomal integrity of frequently dividing cells. It turns dormant in most somatic cells during adulthood. However, in cancer cells, telomerase gets reactivated and works tirelessly to maintain the length of telomeres, leading to immortality of cells. Hence, in this study, we have used a combined ligand-based and structure based drug design approach for the identification of novel telomerase inhibitors as anti-cancer agents. We have generated ligand-based QSAR models and structure-based pharmacophores models, according our recent MYSHAPE approach (1), and validated exhaustively. The validated models were used for screening our in house database. A total of 200 hits, obtained through various in silico screening techniques, were filtered to 25 compounds using docking studies. Molecular dynamics simulations were carried out to compare the binding mode and stability of the complexes of Telomerase bound to known inhibitors and the top ranked hits. The results obtained in this study gave assurance about the identified hits as prospective inhibitors of telomerase. Selected hits were synthetized and they are currently screened for inhibitory activity
Molecular modelling studies on dopamine-amino acid conjugates as potential dopaminergic modulators
No full textn
IL DNA PUÒ ANCORA ESSERE CONSIDERATO UN BERSAGLIO D’ELEZIONE PER LO SVILUPPO DI NUOVI FARMACI ANTITUMORALI?
No full textSynthesis and antiproliferative activity of Naphtalenyl substituted 1,2-dihydropyrazol-5-one and related fused tetrazine
No full textIn recent years, besides the main field of nonsteroidal anti-inflammatory agents, the interest towards pyrazolone derivatives has been renewed because of their wide biological and pharmacological applications [1]. Currently, particular attention is focused on such a class of compounds due to the affinity with sigma receptor and their relationship with cancer [2].To these purposes we planned to design, synthesize and evaluate the antiproliferative activity (MTS assays) of a new series of 3-methyl-2-(1-R-naphthalen-2-yl)-1,2-dihydropyrazol-3-one derivatives 1 against HeLa, MCF-7, LAN-5, Caco2 in order to explore their anticancer potential. Additionally, further elaboration of the amino derivative 1 led to the tetracycle 2, possessing a reactive tetrazinone core which conferred valuable antiproliferative activity as previously reported [3]. Synthesis and biological results will be presented.
[1] G. Mariappan, B.P. Saha, L. Sutharson, Anki, S. Garg, L. Pandey, D. Kumar, J. Pharm. Res., 2010, 3(12), 2856.
[2] E. Aydar, C.P. Palmer, M. B. A. Djamoz, Cancer Res., 2004, 64, 5029.
[3] A.M., Almerico, F. Mingoia, P. Diana, P. Barraja, A. Lauria, A. Montalbano, G Cirrincione, G. Dattolo, J. Med. Chem., 2005, 48, 2859
Recent advances on CDK inhibitors: An insight by means of in silico methods
No full textThe cyclin dependent kinases (CDKs) are a small family of serine/threonine protein kinases that can act as a potential therapeutic target in several proliferative diseases, including cancer. This short review is a survey on the more recent research progresses in the field achieved by using in silico methods. All the "armamentarium" available to the medicinal chemists (docking protocols and molecular dynamics, fragment-based, de novo design, virtual screening, and QSAR) has been employed to the discovery of new, potent, and selective inhibitors of cyclin dependent kinases. The results cited herein can be useful to understand the nature of the inhibitor-target interactions, and furnish an insight on the structural/molecular requirements necessary to achieve the required selectivity against cyclin dependent kinases over other types of kinases
The in silico fischer lock-and-key model: The combined use of molecular descriptors and docking poses for the repurposing of old drugs
No full textNot 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
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
- …
