1,721,166 research outputs found
From extended spectrum beta-lactamases to carbapenemases: the never ending challenge against Gram-negative bacteria
No full textEditorial for the special issue: "From extended spectrum beta-lactamases to carbapenemases: the never ending challenge against Gram-negative bacteria
How computational methods try to disclose the estrogen receptor secrecy - Modelling the flexibility
No full textThe Estrogen Receptor (ER) is a ligand activated transcription factor involved in numerous fundamental biological processes as in many important diseases and malfunctions. Since 1998, when the first structure of the ER ligand binding domain complexed with 17 beta-estradiol (E2) was released, the number of ER alpha and ER beta crystallographic structures constantly increased. Nevertheless, little is still known about several fundamental events that govern the regular biological activity, or that modulate the transcription response following the interaction of the receptor with xenobiotic compounds. Moreover, the peculiar flexibility of the receptor characterized by two levels of conformational changes, i.e slight adjustments of binding pocket residues side chains, and more significant displacement of helix 12, moving from a close/agonist-like to an open/antagonist-like position, makes experimental approaches unable to properly describe and predict the receptor conformational equilibrium. Which is the most probable structure of the unbound receptor? How do biological ligands enter the receptor? How does the tissue-related pull of coactivators and corepressors affect the puzzling conformational equilibrium of the receptor? Since most of these questions still do not have an answer. A proper description of the structure-activity relationship and of the pharmacophoric properties of the binding pocket would be of paramount importance in order to design new agonist and antagonist molecules, and to understand how diverse xenobiotic compounds can alter the conformational equilibrium of the receptor, inducing estrogenic or anti-estrogenic effects. In this review we report the most relevant computational approaches, both theoretical and applicative, and the latest proposed models
FADB: a food additive molecular database for in silico screening in food toxicology.
No full textA crucial limit to in silico preliminary toxicological evaluations in the "food safety" area is the lack of a specific, efficient and available free dataset of 3D small molecules. In this direction, we present the first version of FADB (Food Additives Data Base), a suitable and freely available food additives dataset. FADB is the 3D version of the EAFUS (Everything Added to Food in the United States) list, a sum of WHO, FAO food additive databases and could be a useful starting material in preliminary stages of toxicological assessments. Molecules in FADB are represented through several chemical and 1D identifies, physical properties and 3D (SD and Mol2 file) file formats. FADB also contains important information about functional uses of chemicals as food additives. The aim of the work is to put together substances potentially relevant to food into a "computational" library for virtual screening and docking studies with interesting scenarios for toxicology
A new approach for investigating protein flexibility based on Constraint Logic Programming. The first application in the case of the estrogen receptor
No full textOpen challenges in structure-based virtual screening: Receptor modeling, target flexibility consideration and active site water molecules description
Full text linkStructure-based virtual screening is currently an established tool in drug lead discovery projects. Although in the last years the field saw an impressive progress in terms of algorithm development, computational performance, and retrospective and prospective applications in ligand identification, there are still long-standing challenges where further improvement is needed. In this review, we consider the conceptual frame, state-of-the-art and recent developments of three critical “structural” issues in structure-based drug lead discovery: the use of homology modeling to accurately model the binding site when no experimental structures are available, the necessity of accounting for the dynamics of intrinsically flexible systems as proteins, and the importance of explicitly consider active site water molecules, and accounting for their possible essential contribution in lead identification and optimization campaigns
Serine racemase: a key player in neuron activity and in neuropathologies
No full textSerine racemase is the pyridoxal 5’-phosphatedependent enzyme that catalyzes L-serine racemisation to D-serine, and L- and D-serine beta-elimination in mammalian brain. D-serine is the essential co-agonist of the N-methyl-D-aspartate receptor, that mediates neurotransmission, synaptic plasticity, cell migration and long term potentiation. High and low D-serine levels have been associated with distinct neuropathologies, agingrelated deficits and psychiatric disorders due to either hyper- or hypo-activation of the receptor. Serine racemase dual activity is regulated by ATP, divalent cations, cysteine nitrosylation, post-translational modifications, and interactions with proteins that bind either at the N- or Cterminus. A detailed elucidation of the molecular basis of catalysis, regulation and conformational plasticity, as well as enzyme and D-serine localization and neurons and astrocytes cross-talk, opens the way to the development of enzyme inhibitors and effectors for tailored therapeutic treatments
Protein Flexibility and Ligand Recognition: Challenges for Molecular Modeling
No full textThe intrinsic dynamics of macromolecules is an essential property to relate the structure of biomolecular systems with their function in the cell. In the field of ligand-receptor recognition, numerous evidences have revealed the limitations of the lock-and-key theory, and the need to elaborate models that take into account the inherent plasticity of biomolecules, such as the induced-fit model or the existence of an ensemble of pre-equilibrated conformations. Depending on the nature of the target system, ligand binding can be associated with small local adjustments in side chains or even the backbone to large-scale motions of structural fragments, domains or even subunits. Reproducing the inherent flexibility of biomolecules has thus become one of the most challenging issues in molecular modeling and simulation studies, as it has direct implications in our understanding of the structure-function relationships, but even in areas such as virtual screening and structure-based drug discovery. Given the intrinsic limitation of conventional simulation tools, only events occurring in short time scales can be reproduced at a high accuracy level through all-atom techniques such as Molecular Dynamics simulations. However, larger structural rearrangements demand the use of enhanced sampling methods relying on modified descriptions of the biomolecular system or the potential surface. This review illustrates the crucial role that structural plasticity plays in mediating ligand recognition through representative examples. In addition, it discusses some of the most powerful computational tools developed to characterize the conformational flexibility in ligand-receptor complexes
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