7,870 research outputs found
Descriptores globales y locales de la reactividad para el diseño de nuevos fármacos anticancerosos basados en cis-platino(II)
Density functional theory was used to investigate the global and local reactivity of some cis-platinum(II) complexes including anticancer drugs, such as cisplatin and carboplatin. Calculated equilibrium geometries at mPW1PW/LANL2DZ* are in close agreement with their available X-ray data. We develop three new local reactivity descriptors: atomic descriptor of philicity, atomic descriptor group and atomic descriptor of philicity group for determining chemical reactivity and selectivity of the studied complexes. This contribution on chemical reactivity allow us to establish qualitative trends, which enable our descriptors for use in rational platinum based anticancer drug design
Computational study of the chemical reactivity properties of bis (trimethyl tetrathiafulvalenyl) thiophene
The chemical reactivity of four bis (trimethyltetrathiafulvalenyl) thiophene is determined by its potential (electronic) energy (hyper) surface. All the quantum chemical calculations have been carried out using DFT level of theory, B3LYP functional and 6-31G(d,p) as basis set. Molecular electrostatic potential (MEP) and HOMO-LUMO energy levels have been performed. The local reactivity descriptor such as Fukui function is also performed to determine the reactive sites within the title molecules. The chemometric methods PCA and HCA were employed to find the subset of variables that could correctly classify the compounds according to their reactivity
A generalized operational formula based on total electronic densities to obtain 3D pictures of the dual descriptor to reveal nucleophilic and electrophilic sites accurately on closed-shell molecules
Indexación: Wiley Online Library. Online Version of Record published before inclusion in an issue http://onlinelibrary.wiley.com/doi/10.1002/jcc.24453/fullBy means of the conceptual density functional theory, the so-called dual descriptor (DD) has been adapted to be used in any closed-shell molecule that presents degeneracy in its frontier molecular orbitals. The latter is of paramount importance because a correct description of local reactivity will allow to predict the most favorable sites on a molecule to undergo nucleophilic or electrophilic attacks; on the contrary, an incomplete description of local reactivity might have serio us consequences, particularly for those experimental chemists that have the need of getting an insight about reactivity of chemical reagents before using them in synthesis to obtain a new compound. In the present work, the old approach based only on electronic densities of frontier molecular orbitals is replaced by the most accurate procedure that implies the use of total electronic densities thus keeping consistency with the essential principle of the DFT in which the electronic density is the fundamental variable and not the molecular orbitals. As a result of the present work, the DD will be able to properly describe local reactivities only in terms of total electronic densities. To test the proposed operational formula, 12 very common molecules were selected as the original definition of the DD was not able to describe their local reactivities properly. The ethylene molecule was additionally used to test the capability of the proposed operational formula to reveal a correct local reactivity even in absence of degeneracy in frontier molecular orbitals.http://onlinelibrary.wiley.com/doi/10.1002/jcc.24453/ful
Reactivity of a Pt(100) cluster modified by adsorption of a nickel tetramer
The aim of this paper is to report a study of the reactivity of Pt(100) cluster and the same system modified by a nickel tetramer towards the atomic hydrogen adsorption. This study was carried out in the framework of density functional theory which provides global and local indexes that can be used to characterize the reactivity. The analyzed reactivity descriptors were: chemical potential, chemical hardness, electrophilicity index and Fukui function. The results showed that the global reactivity descriptor predicts that the platinum cluster modified by nickel is more reactive than the pure platinum cluster and that the local Fukui function provides information about the most susceptible site to electrophilic attack in platinum cluster.Instituto de Investigaciones FisicoquÃmicas Teóricas y Aplicada
Reactivity of a Pt(100) cluster modified by adsorption of a nickel tetramer
The aim of this paper is to report a study of the reactivity of Pt(100) cluster and the same system modified by a nickel tetramer towards the atomic hydrogen adsorption. This study was carried out in the framework of density functional theory which provides global and local indexes that can be used to characterize the reactivity. The analyzed reactivity descriptors were: chemical potential, chemical hardness, electrophilicity index and Fukui function. The results showed that the global reactivity descriptor predicts that the platinum cluster modified by nickel is more reactive than the pure platinum cluster and that the local Fukui function provides information about the most susceptible site to electrophilic attack in platinum cluster.Instituto de Investigaciones FisicoquÃmicas Teóricas y Aplicada
Modeling reactivity to biological macromolecules with a deep multitask network
Most
small-molecule drug candidates fail before entering the market,
frequently because of unexpected toxicity. Often, toxicity is detected
only late in drug development, because many types of toxicities, especially
idiosyncratic adverse drug reactions (IADRs), are particularly hard
to predict and detect. Moreover, drug-induced liver injury (DILI)
is the most frequent reason drugs are withdrawn from the market and
causes 50% of acute liver failure cases in the United States. A common
mechanism often underlies many types of drug toxicities, including
both DILI and IADRs. Drugs are bioactivated by drug-metabolizing enzymes
into reactive metabolites, which then conjugate to sites in proteins
or DNA to form adducts. DNA adducts are often mutagenic and may alter
the reading and copying of genes and their regulatory elements, causing
gene dysregulation and even triggering cancer. Similarly, protein
adducts can disrupt their normal biological functions and induce harmful
immune responses. Unfortunately, reactive metabolites are not reliably
detected by experiments, and it is also expensive to test drug candidates
for potential to form DNA or protein adducts during the early stages
of drug development. In contrast, computational methods have the potential
to quickly screen for covalent binding potential, thereby flagging
problematic molecules and reducing the total number of necessary experiments.
Here, we train a deep convolution neural networkî—¸the XenoSite
reactivity modelî—¸using literature data to accurately predict
both sites and probability of reactivity for molecules with glutathione,
cyanide, protein, and DNA. On the site level, cross-validated predictions
had area under the curve (AUC) performances of 89.8% for DNA and 94.4%
for protein. Furthermore, the model separated molecules electrophilically
reactive with DNA and protein from nonreactive molecules with cross-validated
AUC performances of 78.7% and 79.8%, respectively. On both the site-
and molecule-level, the model’s performances significantly
outperformed reactivity indices derived from quantum simulations that
are reported in the literature. Moreover, we developed and applied
a selectivity score to assess preferential reactions with the macromolecules
as opposed to the common screening traps. For the entire data set
of 2803 molecules, this approach yielded totals of 257 (9.2%) and
227 (8.1%) molecules predicted to be reactive only with DNA and protein,
respectively, and hence those that would be missed by standard reactivity
screening experiments. Site of reactivity data is an underutilized
resource that can be used to not only predict if molecules are reactive,
but also show where they might be modified to reduce toxicity while
retaining efficacy. The XenoSite reactivity model is available at http://swami.wustl.edu/xenosite/p/reactivity
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