1,721,082 research outputs found
Computational methods applied to the discovery of stem cell factor ligands
No full textA computational study of the stem cell factor (SCF) and potential ligands was carried out starting with a crystallographic model deposited in the protein data bank. The inhibition of the SCF dimerization equilibrium was considered as the rationale for the lead identification of specific ligands. A preliminary molecular dynamics characterization of the SCF dimer allowed to verify the most flexible loop involved in the dimeric area. Then a virtual screening, coupled with energy minimization in GB/SA water, scored the compounds implemented in the NCI diversity molecular database. Ten top ranked ligands were analyzed considering both the SCF loop perturbation in the dimerization area and the network of intermolecular hydrogen bonds. Among these ten compounds two natural agents were identified. The computational work revealed useful new insights for rational design of novel SCF dimerization inhibitors
GRID-based three-dimensional pharmacophores II: PharmBench, a benchmark data set for evaluating pharmacophore elucidation methods
No full textTo date, published pharmacophore elucidation approaches typically use a handful of data sets for validation: here, we have assembled a data set for 81 targets, containing 960 ligands aligned using their cocrystallized protein targets, to provide the experimental "gold standard". The two-dimensional structures are also assembled to remove conformational bias; an ideal method would be able to take these structures as input, find the common features, and reproduce the bioactive conformations and their alignments to correspond with the X-ray-determined gold standard alignments. Here we present this data set and describe three objective measures to evaluate performance: the ability to identify the bioactive conformation, the ability to identify and correctly align this conformation for 50% of the molecules in each data set, and the pharmacophoric field similarity. We have applied this validation methodology to our pharmacophore elucidation method FLAPpharm, that is published in the first paper of this series and discuss the limitations of the data set and objective success criteria. Starting from two-dimensional structures and producing unbiased models, FLAPpharm was able to identify the bioactive conformations for 67% of the ligands and also to produce successful models according to the second metric for 67% of the Pharmbench data sets. Inspection of the unsuccessful models highlighted the limitation of this root mean square (rms)-derived metric, since many were found to be pharmacophorically reasonable, increasing the overall success rate to 83%. The PharmBench data set is available at http://www.moldiscovery.com/PharmBench , along with a web service to enable users to score model alignments coming from external methods in the same way that we have presented here and, therefore, establishes a pharmacophore elucidation benchmark data set available to be used by the community
(E)-3-Heteroarylidenechroman-4-ones as potent and selective monoamine oxidase-B inhibitors
Full text linkA series of (E)-3-heteroarylidenechroman-4-ones (1a-r) was designed, synthesized and investigated
in vitro for their ability to inhibit the enzymatic activity of both human monoamine oxidase (hMAO)
isoforms, hMAO-A and hMAO-B. All the compounds were found to be selective hMAO-B inhibitors
showing IC50 values in the nanomolar or micromolar range. (E)-5,7-Dichloro-3-{[(2-(dimethylamino)
pyrimidin-5-yl]methylene}chroman-4-one (1c) was the most interesting compound identified in this
study, endowed with higher hMAO-B potency (IC50 1⁄4 10.58 nM) and selectivity (SI > 9452) with respect
to the reference selective inhibitor selegiline (IC50 1⁄4 19.60 nM, IC50 > 3431). Molecular modelling studies
were performed for rationalizing at molecular level the target selective inhibition of our compounds,
revealing a remarkable contribution of hydrogen bond network and water solvent
Derivati indolilalchilaminici. Approccio razionale alla progettazione di nuovi ligandi sigma
No full textAloysia citrodora Polyphenolic Extract: From Anti-Glycative Activity to In Vitro Bioaccessibility and In Silico Studies
Full text linkBackground: The in vivo accumulation of Advanced Glycation End products (AGEs)
is associated with the development of several chronic aging-related and degenerative
diseases, as they alter protein structures and activate oxidative and inflammatory processes
through interactions with the receptor for AGEs (RAGE). Plant secondary metabolites
play a key role in counteracting the glycation process through various mechanisms of
action. Therefore, Aloysia citrodora leaf polyphenolic extract could represent a source
of anti-glycative compounds. Methods: The methanolic extract was characterized by
RP-HPLC-DAD-MSn, and its anti-glycative properties were investigated using several
in vitro assays mimicking the different steps of the glycation reaction. In parallel, molecular
docking studies were carried out to evaluate potential interactions between the identified
metabolites and RAGE. Furthermore, A. citrodora metabolites’ stability under simulated
in vitro digestion was assessed, and the anti-glycative activity of the bioaccessible fraction
was investigated. Results: A. citrodora extract, rich in iridoid glycosides, phenylethanoid
glycosides, and flavones, strongly inhibited AGE formation (from 10% to 100%) in both
the middle and end step of the reaction and had high methylglyoxal and glyoxal trapping
capacity. However, the digestion process affected extract stability, particularly under
intestinal conditions, yielding an overall bioaccessibility of about 40% and leading to a
subsequent reduction in anti-glycative properties. Finally, molecular modeling analysis
highlighted the ability of the studied metabolites to bind RAGE. Conclusions: A. citrodora
represents a promising source of natural anti-glycative agents with potential applications
as food ingredients. However, it is essential to improve the extract bioaccessibility and to
preserve its anti-glycative properties by developing a suitable formulatio
Computer-aided molecular design of asymmetric pyrazole derivatives with exceptional enantioselective recognition towards the Chiralcel OJ-H stationary phase.
No full textConformational search of antisense nucleotides
No full textA preliminary MMFF implementation of selenium atom parameters necessary to model the nucleoside I is reported. X-ray structures of two compounds I and 2 have been used as references. Ab initio methods have been adopted for checking torsional energy profile and charge distribution. Monte Carlo calculations and energy minimization in solvation complete the conformational search. (C) 2001 Elsevier Science Ltd. All rights reserved
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