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I B Bersuker

Publications and source records attributed to I B Bersuker.

9 recordsLinked to original sources
PubMed2003

Pharmacophore identification and quantitative bioactivity prediction using the electron-conformational method.

A review of the Electron-Conformational (EC) method of pharmacophore (Pha) identification and quantitative bioactivity prediction in drug design and toxicology is presented, which includes the latest advances and improvements of the method as a whole and details of its realization with illustration of results. In the first part devoted to Pha identification the data of conformational analysis and electronic structure calculation of each of the molecules in the training set are used to construct EC matrices of congruity (ECMC) that include atomic interaction indices as diagonal elements, and bond orders and interatomic distances as off-diagonal elements. Multiple comparisons of the ECMC's of the active compounds between themselves and with those of inactive compounds allows one to separate a relatively small number of matrix elements that within certain tolerances are common to all the ECMC's of the active compounds, while not present in the same combination in the inactive compounds. This is the EC submatrix of activity that represent the Pha, while the tolerances characterize the Pha flexibilities. Distinguished from QSAR approaches, the Pha is obtained here by computational (non-statistical) methods only. The second part of the problem, quantitative activity prediction, is based on using the Pha flexibilities together with the anti-Pha shielding and other auxiliary groups influence in a parameterization and regression analysis procedure that allows for quantitative prediction. An original approach is suggested that side steps the multi-conformational implications. This post-Pha problem is similar to a QSAR approach with special physically transparent descriptors that allow one to avoid chance correlations in the regression procedure. Illustration of the method is given for several drug design problems in which, where sufficiently accurate experimental data are available, the identification of the Pha as a necessary condition of activity is almost 100% correct, while quantitative activity prediction is near to the accuracy of the experimental data, 80% - 90%.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1999

An electron-conformational method of identification of pharmacophore and anti-pharmacophore shielding: application to rice blast activity.

In extension and improvement of previous results, a novel method is worked out for pharmacophore identification and activity prediction in structure-activity relationships. In this method, as in our previous works, each molecular system (conformation) of the training set is described by a matrix with both electron structural parameters (atomic charges, bond orders, etc.) and interatomic distances as matrix elements. This description includes a rather full geometry of charge and/or reactivity distribution thus providing a much better representation of the molecular properties in their interaction with the target. By multiple comparison of these matrices for the active and inactive compounds of the training set, a relatively small number of matrix elements are revealed that are common for all the active compounds and are not present in the same combination in the inactive ones. In this way a set of electronic and geometry parameters is obtained that characterize the pharmacophore (Pha). A major improvement of this scheme is reached by introducing the anti-pharmacophore shielding (APS) and a proper treatment of the conformational problem. The APS is defined as molecular groups and competing charges outside the basic skeleton (the Pha plus the inert neighbor atoms that do not affect the activity) that hinder the proper docking of the Pha with the bioreceptor thus diminishing (partially or completely) the activity. A simple empirical formula is derived to estimate the relative contribution of APS numerically. Two main issues are most affected by the APS: (1) the procedure of Pha identification is essentially simplified because only a small number of molecular systems with the highest activity and simplest structures (systems without APS) should be tried for this purpose; (2) with the APS known numerically, we can make a quantitative (or semiquantitative) prediction of relative activities. The contributions of different conformations (of the same molecular system) that possess the Pha and different APS is taken into account by means of a Boltzmann distribution at given temperatures. Applied to an example, rice blast activity, this approach proved to be rather robust and efficient. In validation of the method, the screening of 39 new compounds yields approximately 100% (within experimental error) prediction probability of the activity qualitatively (yes, no), and with r2 = 0.66 quantitatively.

Drug Design↗
PubMed1988

Structural and electronic origin of meat odour of organic hetero-atomic compounds.

By means of the electron-topologic approach suggested earlier, the structural and electronic features favouring meat odour occurrence are evaluated using 77 organic compounds with known odorant properties as a basis for primary logico-structural analysis. A general fragment of the type XH2 (where X = S, O, N is a hetero-atom) with a certain electronic structure and conformational property is shown to be responsible for the meat odour. The results obtained allow for a prognosis of odorant compounds and their purposeful synthesis.

Animals↗
PubMed1985

[Structural traits of the antioxidant and fungicidal activity of steroid glycosides].

To investigate the origin of antioxidant and antifungal properties of steroid glycosides (SG), a logico-structural analysis of the structure-activity relationships has been performed for 70 compounds using a set of computer programs STRAC. The following structural features responsible for antioxidant activity are revealed: 1) furostanol type of aglycon; 2) the presence of more than 4 branched monosaccharides in the carbohydrate chain; 3) the presence of glucose at C26 and OH-groups in the genin part of SG. Most characteristic for antifungal activity is the fragment genin-C3-Gal-Glc-Glc-Rha..., as well as the spirostanol type of aglycon. The computer analysis provided the basis for predicting a type of biological activity for 12 new compounds of the SG class.

Antifungal Agents↗
PubMedDate not supplied

Improved electron-conformational method of pharmacophore identification and bioactivity prediction. Application to angiotensin converting enzyme inhibitors.

The electron-conformational (EC) method of pharmacophore (Pha) identification and bioactivity prediction, suggested earlier, is given here two major improvements. First, an atomic index of orbital and charge controlled interaction is introduced to better represent the ligand (substrate) in its interaction with the bioreceptor. Second, the multiconformational problem is considered in view of ligand-receptor binding states, resulting in essential simplification of the expression of bioactivity. The details of the improved EC method are demonstrated in application to the problem of angiotensin converting enzyme (ACE) inhibitors. The Pha of the latter is identified by separation of the heavily populated conformations of the chosen 51 compounds (the training set), calculation of the electronic structure, construction of their EC matrixes of congruity, and processing of the latter in comparison with the activities to reveal a common submatrix of all the active only compounds that describes the Pha. The latter contains three oxygen atoms plus a fourth atom X = S, N, O at certain interatomic distances and with restricted electronic parameters (within assumed tolerances), the position of the atom X being more changeable from one active compound to another. For quantitative prediction of the bioactivity, an expression is deduced which takes into account the duly parametrized influence of auxiliary groups (AG) which, being positioned outside the Pha, either diminish the activity (antipharmacophore shielding) or enhance it. It is shown that in case of many conformations of the same compound only one of them, that of the lowest energy which has the Pha, should be parametrized. The 15 parameters chosen to represent the AG in case of ACE inhibitors are weighted by variational (adjustable) coefficients which are determined from a regression treatment of the calculated versus known activities in the training set. Then the formulas with known coefficients are used to validate the method by calculating the bioactivity of other compounds not used in the training set. The prediction of the activity proved to be more than 90% (within experimental error and available compounds) qualitatively (yes, no) and about 60%-70% quantitatively.

Angiotensin-Converting Enzyme Inhibitors↗
PubMedDate not supplied

[Electron factors in peroxidase properties and the mechanism of activation of oxygen with heme-containing proteins].

A quantum-chemical calculation was carried out for the electronic structure of coordination compounds of general formula FeP (L1) (L2) (P-porphine; L1-imidazole or imidazolate; L2-CO, O2 or is absent), modelling the active sites of number of hemoproteins. The elucidation of electronic structures of the complexes under consideration explains the similar shapes and band positions of optical absorption and magnetic circular dichroism spectra of oxy- and carboxycomplexes of myoglobin, hemoglobin, and peroxidase. It is shown that the Coulomb repulsion between electrons of the lone pair of the imidazolate distal nitrogen leads to the transfer of the electronic density from this ligand to the dioxygen. This results in the strong dioxygen activation leading, in particular, to the high catalytical activity of peroxidase.

Apoenzymes↗