Search results for "Computer Science Applications"
showing 10 items of 3993 documents
On the Applicability of Elastic Network Normal Modes in Small-Molecule Docking
2012
Incorporating backbone flexibility into protein-ligand docking is still a challenging problem. In protein-protein docking, normal mode analysis (NMA) has become increasingly popular as it can be used to describe the collective motions of a biological system, but the question of whether NMA can also be useful in predicting the conformational changes observed upon small-molecule binding has only been addressed in a few case studies. Here, we describe a large-scale study on the applicability of NMA for protein-ligand docking using 433 apo/holo pairs of the Astex data sets. On the basis of sets of the first normal modes from the apo structure, we first generated for each paired holo structure a…
Homology models of melatonin receptors: challenges and recent advances
2013
Melatonin exerts many of its actions through the activation of two G protein-coupled receptors (GPCRs), named MT1 and MT2. So far, a number of different MT1 and MT2 receptor homology models, built either from the prototypic structure of rhodopsin or from recently solved X-ray structures of druggable GPCRs, have been proposed. These receptor models differ in the binding modes hypothesized for melatonin and melatonergic ligands, with distinct patterns of ligand-receptor interactions and putative bioactive conformations of ligands. The receptor models will be described, and they will be discussed in light of the available information from mutagenesis experiments and ligand-based pharmacophore …
Receptor-guided 3D-QSAR approach for the discovery of c-kit tyrosine kinase inhibitors
2012
Studies of the the three-dimensional quantitative structure–activity relationships for ninety-five c-kit tyrosine kinase inhibitors were performed. Based on a co-crystallized compound (1 T46), known inhibitors were aligned with c-kit by induced-fit docking, and multiple training/test set splitting was performed to validate the selected pharmacophore model. The best pharmacophore model consisted of five features: one hydrogen-bond donor and four aromatic rings. Reliable statistics were obtained (R 2 = 0.95, R pred 2 = 0.75), and the model was validated by using it to select c-kit inhibitors from a database; 82.1% of the hits it retrieved were active. Accordingly, our model can be reliably u…
Identification of New Templates for the Synthesis of BEA, BEC, and ISV Zeolites Using Molecular Topology and Monte Carlo Techniques
2020
The presence of organic structure directing agents (templates) in the synthesis of zeolites allows the synthesis to be directed, in many cases, toward structures in which there is a large stabilization between the template and the zeolite micropore due to dispersion interactions. Although other factors are also important (temperature, pH, Si/Al ratio, etc.), systems with strong zeolite-template interactions are good candidates for an application of new computational algorithms, for instance those based in molecular topology (MT), that can be used in combination with large databases of organic molecules. Computational design of new templates allows the synthesis of existing and new zeolites …
Structural, chemical topological, electrotopological and electronic structure hypotheses.
2003
The first important hypothesis in the prediction of properties of synthesized molecules is the structural hypothesis. In the study of drug-receptor interactions, the case where the three-dimensional structure of the receptor is known allows the application of molecular simulation and energy calculations to estimate the binding affinity for a proposed series of compounds. The chemical topological hypothesis permits the description of molecular structures without using concepts such as force or energy. These notions would not be as dominant as supposed since they should be able to be deduced from topology. Although topological descriptors are able to describe specific physicochemical properti…
Computational Methods in Developing Quantitative Structure-Activity Relationships (QSAR): A Review
2006
Virtual filtering and screening of combinatorial libraries have recently gained attention as methods complementing the high-throughput screening and combinatorial chemistry. These chemoinformatic techniques rely heavily on quantitative structure-activity relationship (QSAR) analysis, a field with established methodology and successful history. In this review, we discuss the computational methods for building QSAR models. We start with outlining their usefulness in high-throughput screening and identifying the general scheme of a QSAR model. Following, we focus on the methodologies in constructing three main components of QSAR model, namely the methods for describing the molecular structure …
String kernels and high-quality data set for improved prediction of kinked helices in α-helical membrane proteins.
2011
The reasons for distortions from optimal α-helical geometry are widely unknown, but their influences on structural changes of proteins are significant. Hence, their prediction is a crucial problem in structural bioinformatics. For the particular case of kink prediction, we generated a data set of 132 membrane proteins containing 1014 manually labeled helices and examined the environment of kinks. Our sequence analysis confirms the great relevance of proline and reveals disproportionately high occurrences of glycine and serine at kink positions. The structural analysis shows significantly different solvent accessible surface area mean values for kinked and nonkinked helices. More important, …
Structural and Functional Basis for Understanding the Biological Significance of P2X7 Receptor
2020
The P2X7 receptor (P2X7R) possesses a unique structure associated to an as yet not fully understood mechanism of action that facilitates cell permeability to large ionic molecules through the receptor itself and/or nearby membrane proteins. High extracellular adenosine triphosphate (ATP) levels—inexistent in physiological conditions—are required for the receptor to be triggered and contribute to its role in cell damage signaling. The inconsistent data on its activation pathways and the few studies performed in natively expressed human P2X7R have led us to review the structure, activation pathways, and specific cellular location of P2X7R in order to analyze its biological relevance. The ATP-…
Efficient virtual screening using multiple protein conformations described as negative images of the ligand-binding site.
2010
The protein structure-based virtual screening is typically accomplished using a molecular docking procedure. However, docking is a fairly slow process that is limited by the available scoring functions that cannot reliably distinguish between active and inactive ligands. In contrast, the ligand-based screening methods that are based on shape similarity identify the active ligands with high accuracy. Here, we show that the usage of negative images of the ligand-binding site, together with shape comparison tools, which are typically used in ligand-based virtual screening, improve the discrimination of active molecules from inactives. In contrast to ligand-based shape comparison, the negative …
Accurate Treatment of Large Supramolecular Complexes by Double-Hybrid Density Functionals Coupled with Nonlocal van der Waals Corrections.
2015
In this work, we present a thorough assessment of the performance of some representative double-hybrid density functionals (revPBE0-DH-NL and B2PLYP-NL) as well as their parent hybrid and GGA counterparts, in combination with the most modern version of the nonlocal (NL) van der Waals correction to describe very large weakly interacting molecular systems dominated by noncovalent interactions. Prior to the assessment, an accurate and homogeneous set of reference interaction energies was computed for the supramolecular complexes constituting the L7 and S12L data sets by using the novel, precise, and efficient DLPNO-CCSD(T) method at the complete basis set limit (CBS). The correction of the bas…