1,720,995 research outputs found
New Perspectives on Machine Learning in Drug Discovery
No full textArtificial intelligence methods, in particular, machine learning, has been playing a pivotal role in drug development, from structural design to the clinical trial. This approach is harnessing the impact of computer-aided drug discovery due to large available data sets for drug candidates and its new and complex manner of information interpretation to identify patterns for the study scope. In the present review, recent applications related to drug discovery and therapies are assessed, and limitations and future perspectives are analyzed
Extensive Molecular Dynamics Simulations Disclosed the Stability of mPGES-1 Enzyme and the Structural Role of Glutathione (GSH) Cofactor
Full text linkA deep in silico investigation of various microsomal prostaglandin E-2 synthase-1 (mPGES-1) protein systems is here reported using molecular dynamics (MD) simulations. Firstly, eight different proteins models (Models A-H) were built, starting from the active enzyme trimer system (Model A), namely that bound to three glutathione (GSH) cofactor molecules, and then gradually removing the GSHs (Models B-H), simulating each of them for 100 ns in explicit solvent. The analysis of the obtained data disclosed the structural role of GSH in the chemical architecture of mPGES-1 enzyme, thus suggesting the unlikely displacement of this cofactor, in accordance with experimentally determined protein structures co-complexed with small molecule inhibitors. Afterwards, Model A was submitted to microsecond-scale molecular dynamics simulation (total simulation time=10 mu s), in order to shed light about the dynamical behaviour of this enzyme at atomic level and to obtain further structural features and protein function information. We confirmed the structural stability of the enzyme machinery, observing a conformational rigidity of the protein, with a backbone RMSD of similar to 3 angstrom along the simulation time, and highlighting the strong active contribution of GSH molecules due to their active role in packing the protein chains through a tight binding at monomer interfaces. Furthermore, the focused analysis on R73 residue disclosed its role in solvent exchange events, probably excluding its function as route for GSH to enter towards the endoplasmic reticulum membrane, in line with the recently reported function of cap domain residues F44-D66 as gatekeeper for GSH entrance into catalytic site
Quantum Mechanical Calculation of NMR Parameters in the Stereostructural Determination of Natural Products
No full textStructural basis for the design and synthesis of selective HDAC inhibitors
No full textHistone Deacetylases are considered promising targets for cancer epigenetic therapy, and small molecules
able to modulate their biological function have recently gained an increasing interest as potential
anticancer agents. In spite of their potential application in cancer therapy, most HDAC inhibitors unselectively
bind the several HDAC isoforms, giving rise to different side-effects. In this context, we have traced
out the structural elements responsible of selective binding for the therapeutically relevant different
HDAC isoforms. The structural analysis has been carried out by molecular modeling, docking in the binding
pockets of HDAC1–4 and HDAC6–8, 36 inhibitors presenting a well defined selectivity for the different
isoforms. As quick proof of evidence, we have designed, synthesized and experimentally tested three
selective ligands. The experimental data suggest that the obtained structural guidelines can be useful
tools for the rational design of new potent inhibitors against selected HDAC isoform
Synthesis and biological activity of cyclotetrapeptide analogues of the natural HDAC inhibitor FR235222
No full textIdentifying toxicity pathways of apomyoglobin amyloid prefibrillar oligomers using a combined proteomic and 1H-NMR metabolomic approach
No full textBio-inspired benzo[k,l]xanthene lignans: synthesis, DNA-interaction and antiproliferative properties
No full textIn this work twelve benzo[k,l]xanthene lignans were synthesized by biomimetic, Mn-mediated oxidative
coupling of caffeic esters and amides. These compounds, bearing different flexible pendants at position
C1/C2 of the aromatic core, interact with DNA in a dual mode, as confirmed by DF-STD NMR analysis
and molecular docking: the planar core acts as a base pair intercalant, whereas the flexible pendants act
as minor groove binders. Their antiproliferative activity was evaluated on a panel of six tumor cell lines:
HT-29, Caco-2, HCT-116 (human colon carcinoma), H226, A549 (human lung carcinoma), and SH-SY5Y
(human neuroblastoma). All compounds under study, except 29, resulted in activity against one or more
cell lines, and the markedly lipophilic esters 13 and 28 showed the highest activity. Compound 13 was
more active than the anticancer drug 5-fluorouracil (5-FU) towards HCT-116 (colon, GI50 = 3.16 μM) and
H226 (lung, GI50 = 4.33 μM) cell lines
40 th "A. Corbella" International Summer School on Organic Synthesis - ISOS 2015
No full textHistone demethylases (HDMs) are epigenetic enzymes that remove a methyl group from histone tails, acting as erasers of the epigenetic code.1 Basing on their enzymatic mechanism, HDMs can be grouped into two classes: FAD-dependent HDMs (including monoaminoxidases) and Jumonji C domain containing HDMs that are Fe2+ and α-ketoglutarate-dependent hydrolases.2 The substrate residues of this latter include H3K4, H3K9, H3K27 and H3K36 at all methylation states. In particular, the focus of this study is JMJD3, that specifically demethylates 'Lys- 27' of histone H3.3 It has been reported that these lysine demethylases (JHDM) are associated with several diseases, such as bladder cancer, prostate carcinoma, breast cancer, Hodgkin lymphoma.4 With the aim of discovering new potential inhibitors of this HDM as attractive candidates for the development of anticancer drugs,4 we have designed and synthesized a small collection of 4-substituted-pyridine-2,6-dicarboxylic acids. These molecules contain as scaffold the dipicolinic acid, which has been selected from a large library of fragments through computational studies, suggesting a good interaction with the catalytic site of JMJD3. The experimental binding affinities of the synthesized molecules towards the target protein are currently under evaluation by Differential Scanning Fluorimetry assay (DSF) and further biological assays.
References
Quantum Chemical Calculation of Chemical Shifts in the Stereochemical Determination of Organic Compounds: A Practical Approach
No full textIn the last decade, quantum chemical approaches have shown their potential in solving chemical problems. This has been mostly due to the ever increasing computational capabilities at a relatively affordable cost, and to a parallel development of user friendly software. While many aspects of molecular structure and dynamics may be solved with the use of classical methods based on empirical force fields, quantum chemistry allows the comprehension of many problems related to the electronic density distribution. In particular, quantum chemistry methods can be applied for calculating the spectroscopic properties of molecules, and the efficient prediction of UV, IR, CD, and NMR spectra have been extensively reported in the last fifteen years. NMR chemical shift calculation by quantum mechanical methods has attracted the interest not only of the theoretical chemists, but also of the experimental NMR spectroscopists. In fact, this kind of approach has been used by our and other research groups as a contribution to the structure elucidation of natural products. We have presented two original methodologies, based on GIAO (gauge including atomic orbitals) quantum-mechanical 13C chemical shift calculations, that have been efficiently employed as a support in the analysis of the NMR data of organic molecules. The first methodology regards the structure validation of natural products by means of GIAO 13C chemical shift calculations, while the second one, based on the same methodology, has been directed to the determination of the relative configuration of flexible compounds. For the interested readers, the most significant applications of quantum chemical calculations of NMR parameters in the resolution of stereochemical problems have been recently reported by us in two reviews. On the other hand, the scope of this chapter is to present a step-by-step guide for the chemical shift calculation of organic compounds in the determination of their relative configuration
Discovery of new erbB4 inhibitors: Repositioning an orphan chemical library by inverse virtual screening
No full textInverse Virtual Screening (IVS) is a docking based approach aimed to the evaluation of the virtual ability of a single compound to interact with a library of proteins. For the first time, we applied this methodology to a library of synthetic compounds, which proved to be inactive towards the target they were initially designed for. Trifluoromethyl-benzenesulfonamides 3-21 were repositioned by means of IVS identifying new lead compounds (14-16, 19 and 20) for the inhibition of erbB4 in the low micromolar range. Among these, compound 20 exhibited an interesting value of IC50 on MCF7 cell lines, thus validating IVS in lead repurposing
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