Nina Nikolova

New developments in a hazard identification algorithm for hormone receptor ligands

Recently we described the Common REactivity PAttern (COREPA) technique to screen data sets of diverse structures for their ability to serve as ligands for steroid hormone receptors [1]. The approach identifies and quantifies similar global and local stereoelectronic characteristics associated with active ligands through a comparison of energeticallyreasonable conformer distributions for selected descriptors. For each stereoelectronic descriptor selected, discrete conformer distributions from a training set of ligands are evaluated and parameter ranges common for conformers from all the chemicals in the training set are identified. The use of discrete partitions of parameter ranges to define common reactivity patterns can, however, influence the outcome of the algorithm. To address this limitation, the original method has been extended by approximating continuous conformer distributions as probability distributions. The COREPA-Continuous (COREPA-C) algorithm assesses the common reactivity pattern of biologicallysimilar molecules in terms of a product of probability distributions, rather than a collection of common population ranges determined by examination of discrete partitions of a distribution. To illustrate the algorithm, common reactivity patterns based on interatomic distance and charge on heteroatoms were developed and evaluated using a set of 28 androgen receptor ligands. Notable attributes of the COREPA-C algorithm include flexibility in establishing stereoelectronic descriptor criteria for identifying active and nonactive compounds and the ability to quantify threedimensional chemical similarity without the need to predetermine a toxicophore or align compounds(s) to a lead ligand.

Conformational Coverage by a Genetic Algorithm

A new approach for coverage of the conformational space by a limited number of conformers is proposed. Instead of using a systematic search whose time complexity increases exponentially with degrees of freedom, a genetic algorithm (GA) is employed to minimize 3D similarity among the conformers generated. This makes the problem computationally feasible even for large, flexible molecules. The 3D similarity of a pair of conformers is assumed to be reciprocal to the root-mean-square (rms) distance between identical atomic sites in an alignment providing its minimum. Thus, in contrast to traditional GA, the fitness of a conformer is not quantified individually but only in conjunction with the population it belongs to. The approach handles the following stereochemical and conformational degrees of freedom:  rotation around acyclic single and double bonds, inversion of stereocenters, flip of free corners in saturated rings, and reflection of pyramids on the junction of two or three saturated rings. The latter tw...

Dynamic 3D QSAR techniques: applications in toxicology

Abstract Two dynamic techniques recently developed to account for conformational flexibility of chemicals in three-dimensional (3D) quantitative structure–activity relationships (QSARs) are presented. A basic assumption underlying both methods is that chemical behavior in complex biological systems is context-dependent. A molecule can exist and interact in a variety of conformations. Selection of the appropriate ‘active’ conformer(s) in QSAR studies is a task as important as the selection of appropriate molecular parameters because multiple conformers of one chemical can differ significantly in the value of their calculated molecular descriptors. In the dynamic approaches for selection of active conformers in correlative QSAR studies, biological activity is modeled as a function of molecular descriptors derived from specifically selected active conformers, rather than as a property derived from the lowest-energy gas-phase conformer. In a recent pattern recognition approach all energetically reasonable conformers are taken into account to derive the common reactivity pattern (COREPA) of structurally diverse but biologically similar chemicals (and ultimately conformers). The COREPA method is based on the assumption that chemicals which elicit similar biological behavior through a common mechanism of interaction with the biological ‘receptor’ of interest, should possess a commonality in the values of their steric and/or electronic parameters, thus yielding a COREPA. Applicability of these techniques, based on the same underlying principles, is illustrated. In addition to the impact of conformational flexibility of chemicals in 3D QSAR models, the applicability of various molecular descriptors is discussed. The proposed classification could be useful as guidance for selection of appropriate molecular parameters for modeling a variety of toxicity endpoints according to the specificity of the underlying interactions.

Rule interpreter: a chemical language for structure-based screening

Abstract A chemical language for definition and use of logical rules in screening of chemical databases is described. The rules are based on user-defined screens, which combine substructure matching with constraints on molecular descriptors, stereochemical configurations and mutual 3D placements of chemical groups. Screens are written in extended SMILES notation with the option to define variant chemical groups and constraints in a single entry. Rules are Boolean logic expressions comprised of screens and preceding rules. Arbitrary decision trees can be constructed by using nested and conditional statements referring to the rules defined. The language was used in a database-integrated QSAR expert system for aquatic toxicity, which exploits the concept of toxicochemical analogues. Another example of its usage addresses the prediction of androgen receptor binding affinity.

BEO Moussala – A New Facility for Complex Environment Studies

The main areas of research at the Basic Environmental Observatory (BEO) Moussala, Rila Mountain, are the aerospace and terrestrial environment. The interactions between cosmic rays and Earth atmosphere, global change parameters and climate research, natural hazards and technological risks are the objectives of the investigations. Real-time measurements of basic parameters of space and atmosphere are carried out. The information is transmitted via a high frequency radio-telecommunication system to the Internet and is stored in a database for further analysis within GAW, EURDEP, EUSAAR and UNBSS international programmes. Ecotoxicological investigations are performed to study the mountain ecosystems. On-line data and detailed information about BEO Moussala are available at: http://beo-db.inrne.bas.bg

BEO Moussala: Complex for Environmental Studies

The main areas of research at the Basic Environmental Observatory (BEO) Moussala, Rila Mountain, are the aerospace and terrestrial environment. The interactions between cosmic rays and the Earth’s atmosphere, global change parameters and climate research, and natural hazards and technological risks are the objectives of the investigations.

Aerosol and gamma background measurements at Basic Environmental Observatory Moussala

Abstract Trans boundary and local pollution, global climate changes and cosmic rays are the main areas of research performed at the regional Global Atmospheric Watch (GAW) station Moussala BEO (2925 m a.s.l., 42°10’45’’ N, 23°35’07’’ E). Real time measurements and observations are performed in the field of atmospheric chemistry and physics. Complex information about the aerosol is obtained by using a threewavelength integrating Nephelometer for measuring the scattering and backscattering coefficients, a continuous light absorption photometer and a scanning mobile particle sizer. The system for measuring radioactivity and heavy metals in aerosols allows us to monitor a large scale radioactive aerosol transport. The measurements of the gamma background and the gamma-rays spectrum in the air near Moussala peak are carried out in real time. The HYSPLIT back trajectory model is used to determine the origin of the data registered. DREAM code calculations [2] are used to forecast the air mass trajectory. The information obtained combined with a full set of corresponding meteorological parameters is transmitted via a high frequency radio telecommunication system to the Internet.

DETECTION OF CORONAL MASS EJECTIONS (CMEs) IN THE PERIOD OF MARCH-MAY 2012 AT MOUSSALA PEAK

A large number of geoeffective solar events were registered during the period of March–May 2012. The events were detected as Forbush effects due to Coronal Mass Ejections (CME) occurring in March–April 2012 and a rare Ground Level Enhancement (GLE) in May, produced by region NOAA 1476 moderately strong (GOES class M5.1) flare at 01:25 UT on 17 May 2012 [1]. The data from permanently operational Cherenkov-water telescope of Basic Environmental Observatory at Moussala are used for observation of those activities. The magnetic IMF disturbances and resulting Forbush decreases were registered with high level of confidence. However, the GLE event detection was not confirmed statistically. The inter-comparison between detector responses of those events is used for preliminary study of the future space weather investigations in the Basic Environmental Observatory at Moussala.