Osman F. Guner

Santa Rosa Junior College · Chemistry Department

Under normal physiological conditions, the kynurenine pathway (KP) plays a critical role in generating cellular energy and catabolizing tryptophan. Under inflammatory conditions, however, there is an upregulation of the KP enzymes, particularly kynurenine 3-monooxygenase (KMO). KMO has garnered much attention due to its production of toxic metaboli...

Cancer is a devastating disease that has plagued humans from ancient times to this day. After decades of slow research progress, promising drug development, and the identification of new targets, the war on cancer was launched in 1972. The P13K/Akt pathway is a growth-regulating cellular signaling pathway, which in many human cancers is over-activa...

Background/aim: The P13K/Akt signaling pathway is a growth-regulating cellular pathway that is constitutively activated in a variety of human cancers. In previous studies, we reported that a solenopsin analog, compound B (MU-06-SC-608-7), shows inhibitory effects on Akt phosphorylation at a key activation site, as well as on proliferation of tumor...

There is increasing support for the potential clinical use of compounds that interact with serotonin 2A (5-HT 2A )receptors. It is therefore of interest to discover novel compounds that interact with 5-HT 2A receptors. In the present study, we used computational chemistry to identify critical ligand structural features of 5-HT 2A receptor binding a...

The P13K/Akt pathway is a growth-regulating cellular signaling pathway that is over-activated in numerous human cancers. A novel series of Akt pathway inhibitors were identified using iterative pharmacophore modeling, energy-based calculations, and property predictions of known Akt inhibitors. Inhibitory effects on activation of Akt and growth of h...

NADPH oxidases (Nox enzymes) are critical mediators of both physiologic and pathophysiologic processes. Nox enzymes catalyze NADPH-dependent generation of reactive oxygen species (ROS), including superoxide and hydrogen peroxide. Until recently, Nox4 was proposed to be involved exclusively in normal physiologic functions. Compelling evidence, howev...

Kynurenine monooxygenase (KMO) is a potential drug target for treatment of neurodegenerative disorders such as Huntington's and Alzheimer's diseases. We have evaluated substituted kynurenines as substrates or inhibitors of KMO from Cytophaga hutchinsonii. Kynurenines substituted with a halogen at the 5-position are excellent substrates, with values...

http://www.fasebj.org/content/29/1_Supplement/768.12.abstract

For over a century since the early 1900s, Paul Ehrlich was credited with originating the concept of pharmacophores. This was challenged by John Van Drie in 2007 due to the fact that Ehrlich did not use the word "pharmacophore" in his writings. Van Drie claimed that the attribution of the pharmacophore concept to Ehrlich was due to an erroneous cita...

Understanding the molecular basis of drug action has been an important objective for pharmaceutical scientists. With the increasing speed of computers and the implementation of quantum chemistry methodologies, pharmacodynamics and pharmacokinetic problems have become more computationally tractable. Historically the former has been the focus of drug...

One of the major reasons for late-stage failure of drug candidates is due to problems uncovered in pharmacokinetics during clinical trials. There is now a general consensus for earlier consideration of these effects in the drug discovery process. Computer-aided design technology provides us with tools to develop predictive models for such pharmacok...

In the past decade, the scientific community has realized the value of three-dimensional (3D) structural information and '3D searching' has started to become an important new methodology for computer-aided drug design. During this time, molecular modeling information generated from various sources has proliferated due to the growing availability of...

The earliest proposed definition of the term pharmacophore was made by Ehrlich (also quoted by Ariëns), who defined it as the molecular framework that carries (phoros) the essential features responsible for a drug (pharmacon) biological activity. More-recent definitions of what a pharmacophore entails have been proposed by various researchers; many...

In this paper, we discuss how we safely exchanged proprietary data between third parties in the early years of predictive ADME/Tox model development. At that time, industry scientists wanted to evaluate predictive models, but were not willing to share their structures with software vendors. At the same time, model developers were willing to run the...

With the reliable use of computer simulations in scientific research, it is possible to achieve significant increases in productivity as well as a reduction in research costs compared with experimental approaches. For example, computer-simulation can substantially enchance productivity by focusing the scientist to better, more informed choices, whi...

Perceiving a pharmacophore is the first essential step towards understanding the interaction between a receptor and a ligand. Once a pharmacophore is established, a beneficial use of it is 3D database searching to retrieve novel compounds that would match the pharmacophore. As the 3D searching technology has evolved over the years, it has been effe...

During the past few years, the introduction of ultra-high-throughput screening and new assay design and detection technologies has exponentially increased the amount and complexity of screening data. Effective use of this data implies a process that begins with assay design. An effective data management system should control a range of processes, f...

With computer-aided drug design established as an integral part of the lead discovery and optimization process, pharmacophores have become a focal point for conceptualizing and understanding receptor-ligand interactions. In the structure-based design process, pharmacophores can be used to align molecules based on the three-dimensional arrangement o...

We developed a procedure that identifies "novel" biologically active compounds that are expected to be distinct from known active compounds with respect to specificity and other such characteristics. The procedure involves mapping a set of known active compounds (training set) onto all possible hydrogen bonding and lipophilic interaction sites of a...

Perceiving a pharmacophore is the first essential step towards understanding the interaction between a receptor and a ligand. Once a pharmacophore is established, a beneficial use of it is 3D database searching to retrieve novel compounds that would match the pharmacophore, without necessarily duplicating the topological features of known active co...

With the explosive growth in the use of the World Wide Web, which provides a 'user-friendly' interface to the Internet, accessing information through Web browsers has become a common task for scientists seeking proprietary or public information. Corporate intranets have evolved as a primary infrastructure for the dissemination and access of proprie...

Searching for conformationally flexible molecules is currently a topic of widespread study. In general, this type of three-dimensional (3D) search can proceed by locating the flexibility information either in a database (by storing multiple conformers or conformational analysis results), or in a search engine (by implementing flexible fitting metho...

The bonding character of the transannular (cross ring) bond between inverted carbons of the most strained structures of the rhombic carbon species and (1.1.1) propellane is examined, with emphasis on the rhombic carbon frame. Rhombic C4, its protonated forms C4H(+) and C4H2(2+), and its linear isomer are studied with the 6-311G(2d,p) basis set and...

While three-dimensional (3D) searching has emerged as a new and promising approach to computer-aided drug design, the issue of “conformational flexibility” remains an important problem. The approaches to handling this issue include considering conformational flexibility: (1) in the database itself (storage of multiple conformers); (2) in the search...

Four Diels-Alder reactions of trans-1,3-pentadiene (trans-piperylene) with acetone, methyl vinyl ketone, methyl acrylate, and acrylonitrile were selected for this study due to their varying epimerization rates previously reported (J. Org. Chem. 1988, 53, 5348). The reaction coordinate of the epimerization process for each reaction is evaluated for...

The ab initio molecular orbital study of the 10 valence electron diberyllium diboride (B2Be2) potential energy hypersurface yields a singlet tetrahedrallike form Is as the global minimum at the HF and MP2/6-31G* levels of theory. At MP4/6-31G* the energy difference of Is with any other isomer is at least 30 kcal/mol. The topological electron densit...

The C3H62+ potential energy surface was studied by ab initio molecular orbital theory employing the 3-21G and 6-31G* basis sets and Møller-Plesset perturbation theory. The protonated allyl cation 1, which formally has two terminal cation centers, and the propylidene dication 3, which has formally both charges located at its central dimethyl-substit...

Ab initio calculations on Li3H ion-pair states and a topological analysis of the charge density of the resulting optimized structures are reported. The global Li3H minimum is a planar C2v structure with H− −Li+3 ion-pair character. The pyramidal C3v structure, which is 21.5 kcal/mol higher in energy (MP2/6-311 + + G**), Although vibrational analysi...

Examination of the potential energy surface of dialane by ab initio MO theory at the MP4(SDTQ)/6-31G**//HF/6-31G* + ZPE level, including nine structures, show the salt-like structures (I) and (II) to be the most stable isomers.

Diels-Alder reaction of trans-1,3-pentadiene (I) with acrolein (II) under various conditions yields predominantly the endo-cycloadducts (III).

B and 2H NMR and FTIR spectroscopic results obtained for B2H6 in FSO3D·SbF5/SO2ClF medium at -78 °C confirm the slow proton/deuterium exchange of B2H6 in this solution.

The potential energy surface of dialane(4), Al2H4, has been studied by ab initio molecular orbital theory at the MP4(SDTQ)/ 6-31G**//HF/6-31G* + ZPE level. Five minima (1, 2, 5, 7, and 8) and three transition structures (3, 6, and 9) were determined at the HF/6-31G* level. The most stable isomers are salt-like structures: i.e., 1 (C3υ), being the f...

The differences in bonding and electronic properties between the MP/6-31G* optimized disilicon dicarbide structures 1 and 2 can be related to bond stretch isomerism, which occurs through a level-crossing mechanism. Their energy differences are calculated at the MP4 and GVB/6-31G* levels. Electron density analysis indicates concentration of charge i...

The slow proton/deuterium exchange of B{sub 2}H{sub 6} in the superacidic FSO{sub 3}D SbF{sub 5}/SO{sub 2}ClF medium at low temperature involving the corresponding isotopomeric diboranonium ions B{sub 2}H{sub 7}{sup +} is reported here. The structure of the B{sub 2}H{sub 7}{sup +} ion has also been probed by ab inito theoretical calculations. The H...

The structures and energies of the binary disilicon dicarbide C2Si2 in the lowest singlet and triplet states have been investigated by ab initio MO theory. Full fourth-order Møller-Plesset (MP4) perturbation theory is employed on HF/6-31G*-optimized geometries. Rhombic dicarbide 5s is the global C2Si2 minimum and 8.5 kcal/mol more stable than the r...

The slow proton/deuterium exchange of BâHâ in the superacidic FSOâD SbFâ/SOâClF medium at low temperature involving the corresponding isotopomeric diboranonium ions BâHâ{sup +} is reported here. The structure of the BâHâ{sup +} ion has also been probed by ab inito theoretical calculations. The H/D exchange is rationalized by the pathway that deuter...

Pair-excitation multiconfigurational self-consistent field (PEMCSCF) treatment of 11 small molecules (LiH, BeH2, BH3, BF, CH4, C2H4, C2H2, CH2O, NH3, H2O, and HF) has been carried out in a minimum basis set of Slater Transform Preuss functions as fitted by six cartesian gaussians (STP-6G). The advantages of accuracy without using a split basis are...

The geometries of acrolein and acrolein complexed with boron trifluoride are optimized by using STO-3G and 4-31G basis sets. The optimized geometries are utilized in STO-3G, STO-6G, STP-6G, 4-31G, and 6-31G calculations. The frontier molecular orbital energies and coefficients obtained from these ab initio calculations are used to explain the role...

The regioselectivity in the Diets-Alder reaction of 1-substituted-1, 3-butadienes can be completely explained by FMO theory when the frontier molecular orbitals of the reactants in the concerted transition state are considered. This excellent agreement between theory and experimental results from the more realistic representation of the ionic polar...

Thesis (Ph. D.)--Virginia Commonwealth University, 1986. Includes bibliographical references (leaves 161-168).