Biomedical subjects

Ernesto Estrada

Publications and source records attributed to Ernesto Estrada.

27 records · Page 2Linked to original sources

PubMed2003

Computer-aided knowledge generation for understanding skin sensitization mechanisms: the TOPS-MODE approach.

The TOPS-MODE (topological substructural molecular descriptors) approach is used to derive models for understanding the molecular structural contribution to skin sensitization. A data set of 93 compounds was used in the development of the models; 29 new skin sensitization values (EC3) are reported here for the first time. The models developed possess high predictivity and have been validated through the use of cross-validation and external validation sets. The models have enabled the formulation of potential new structural alerts far faster and using less data than typically required by traditional approaches. Structural contributions to skin sensitization for various classes of chemicals are presented on the basis of bond contributions. The models have also been able to identify potential structural alerts for chemicals requiring metabolic activation.

Animals↗

PubMed2002

Characterization of the folding degree of proteins.

MOTIVATION: The characterization of the folding degree of chains is central to the elucidation of structure--function relationships in proteins. Here we present a new index for characterizing the folding degree of a (protein) chain. This index shows a range of features that are desirable for the study of the relation between structure and function in proteins. RESULTS: A novel index characterizing the folding degree of (protein) chains is developed based on the spectral moments of a matrix representing the dihedral angles (phi, omega and epsilon) of the protein main chain. The proposed index is normalized to the chain size, is not correlated to the gyration radius of the backbone chain and is able to distinguish between structures for which the sum of the main-chain dihedral angles is identical. The index is well correlated to the percentages of helix and strand in proteins, shows a linear dependence with temperature changes, and is able to differentiate among protein families. AVAILABILITY: On request from the author.

Amino Acid Sequence↗

PubMedDate not supplied

In silico studies toward the discovery of new anti-HIV nucleoside compounds with the use of TOPS-MODE and 2D/3D connectivity indices. 1. Pyrimidyl derivatives.

Computational approaches are developed to design or rationally select, from structural databases, pyrimidyl nucleosides with anti-HIV activity. A data set of 141 nucleoside derivatives was selected from literature, and a discriminant function was derived with the use of TOPS-MODE descriptors. The model is able to classify correctly 83% of the compounds in a training set and 88.5% in a cross-validation set. The use of an external prediction set selected from the most recent literature proved that the model has good predictive ability, with a good classification of 85% of the compounds in this set. This model permitted the structural interpretation of the anti-HIV activity of these nucleoside analogues. This interpretation is formulated as several rules concerning the influence of several structural features on the activity/inactivity of such compounds. A QSAR model for the most active compounds was developed with the combined use of 2D and 3D connectivity indices. This model explains 88% of the variance in the activity of these compounds in MT4 assay. The combination of both models will permit the selection of pyrimidyl nucleoside leads and their optimization to improve the potency of the selected ones.

Anti-HIV Agents↗

PubMedDate not supplied

What are the limits of applicability for graph theoretic descriptors in QSPR/QSAR? Modeling dipole moments of aromatic compounds with TOPS-MODE descriptors.

The numerous possibilities of using graph theoretic descriptors in QSPR/QSAR are analyzed, and some misunderstandings on the role of this theoretical approach in chemistry are clarified. Principal component analysis is used to obtain a property space for several physicochemical properties of aromatic compounds. It is proved that most of the QSPR applications of the graph-theoretic structure descriptors are concentrated to the description of properties in a very limited region of this property space. Here, we show that graph-theoretic approaches are also applicable to the modeling of physicochemical properties that are far away from this region traditionally studied. The molecular dipole moments of benzene derivatives, mono-, ortho-, meta-, and para-susbtituted, are modeled by using the Topological Sub-Structural Molecular Design (TOPS-MODE) approach. The TOPS-MODE approach used permits to calculate group dipole moments that are given for several substituents. The differences between these group dipoles and those obtained by simple difference between experimental values are analyzed. Some difficulties arising from this traditional way of deriving substituent constants are identified and analyzed.

Journal Article↗

PubMedDate not supplied

From knowledge generation to knowledge archive. A general strategy using TOPS-MODE with DEREK to formulate new alerts for skin sensitization.

A general strategy for knowledge flow concerning skin sensitization based on the combined use of TOPS-MODE and DEREK expert system is proposed. TOPS-MODE is used as a knowledge generator, while DEREK represents the knowledge archive. A TOPS-MODE classification model allows the identification of structural fragments and groups responsible for strong/moderate skin sensitization. These structural contributions are sorted, analyzed, and graphically displayed in an appropriate way allowing the identification of several structural alerts for skin sensitization. Nine structural alerts already implemented in DEREK are identified using this strategy. They comprise, among others, alkyl halides, aldehydes, alpha,beta-unsaturated compounds, aromatic amines, phenols, hydroquinone, isothiazolinone, and alkyl sulfonates. Four new hypotheses are generated using TOPS-MODE structural contributions to skin sensitization, which are not recognized as structural alerts by DEREK. They include the reduction of aromatic nitro groups and epoxidation reaction of double bonds as metabolic activation steps that can lead to reactive haptens which can trigger the skin sensitization mechanism. Another new alert is based on 1,2,5-thiadiazole-1,1-dioxide for which we have identified a possible mechanism explaining its strong skin sensitization profile. It is based on the existence of a tautomeric equilibrium and further reaction with nucleophiles, which are both supported by experimental evidence. Finally, we have identified a possible new mechanism for the skin sensitization of nonreactive compounds, which involves the formation of noncovalent complexes with proteins in a processing- and metabolism-independent way.

Journal Article↗

PubMedDate not supplied

A protein folding degree measure and its dependence on crystal packing, protein size, secondary structure, and domain structural class.

Comparing two or more protein structures with respect to their degree of folding is common practice in structural biology despite the fact that there is no scale for a folding degree. Here we introduce a formal definition of a folding degree, capable of quantitative characterization. This enables ordering among protein chains based on their degree of folding. The folding degree of a data set of 152 representative nonhomologous proteins is then studied. We demonstrate that the variation in the folding degree seen for this data set is not due to crystallization artifacts or experimental conditions, such as resolution, refinement protocol, pH, or temperature. A good linear relationship is observed between the folding degree and the percentages of secondary structures in the protein. The folding degree is able to account for the small changes produced in the structure due to crystal packing and temperature. Automating the classification of proteins into their respective structural domain classes, namely mainly-alpha, mainly-beta, and alpha-beta, is also possible.

Computational Biology↗

PubMedDate not supplied

In silico studies toward the discovery of new anti-HIV nucleoside compounds through the use of TOPS-MODE and 2D/3D connectivity indices. 2. Purine derivatives.

The TOPological Substructural MOlecular DEsign (TOPS-MODE) approach has been used to predict the anti-HIV activity in MT-4 assays (Estrada et al., 2002) of a diverse range of purine-based nucleosides. A database of 206 nucleosides has been selected from the literature and a theoretical virtual screening model has been developed. The model is able of discriminating between compounds that have anti-HIV activity and those that do not, with a good classification level of 85% in the training and 82.8% in the cross-validation series. On the basis of the information generated by the model, the correct classification of practically 80% of compounds from an external prediction set has been achieved using the theoretical model. Furthermore, the contribution of a range of molecular fragments to the pharmacological action has been calculated and this could provide a powerful tool in the design of nucleoside analogues that show activity against the HIV. Finally, a QSAR model has been developed that allows quantitative data to be obtained regarding the pharmacological potency shown by this type of compound.

Anti-HIV Agents↗

PubMedDate not supplied

An integrated in silico analysis of drug-binding to human serum albumin.

Approaches such as quantitative structure-activity relationships (QSAR) and molecular modeling are integrated with the study of complex networks to understand drug binding to human serum albumin (HSA). A robust QSAR model using the topological substructural molecular descriptors/design (TOPS-MODE) approach has been derived and shows good predictability and interpretability in terms of structural contribution to drug binding to HSA. A perfect agreement exists between the group/fragment contributions found by TOPS-MODE and the specific interactions of drugs with HSA. These results indicate a preponderant contribution of hydrophobic regions of drugs to the specific binding to drug-binding sites 1 and 2 in HSA and specific roles of polar groups which anchor drugs to HSA binding sites. The occurrence of fragments contributing to drug binding to HSA can be represented by complex networks. The fragment-to-fragment complex network displays "small-world" and "scale-free" characteristics and in this way is similar to other complex networks including biological, social, and technological networks. A small number of fragments appear very frequently in most drugs. These molecular "empathic" fragments are good candidates for guiding future drug discovery research.

Algorithms↗

PubMedDate not supplied

Order from chaos: observing hormesis at the proteome level.

We report on an observed regularity in the overall response of cell proteome under influence of different doses of a peroxisome proliferator. Our analysis for the first time demonstrates presence of hormesis at the cellular level. It is shown that despite the fact that the response of individual proteins remains unpredictable, the perturbation of proteome as a whole (measured as the average departure of protein abundances from the corresponding values of the control group) shows regularity: It initially decreases, reaches a minimum, and then increases as the concentration of the used proliferator continue to increase. The work is based on the available data of Anderson at al. on the effects of peroxisome proliferator LY171883 on protein abundances in mouse liver when administrated at different concentrations.

Acetophenones↗