A hybrid approach for addressing ring flexibility in 3D database searching

A hybrid approach for flexible 3D database searching is presented that addresses the problemof ring flexibility. It combines the explicit storage of up to 25 multiple conformations ofrings, with up to eight atoms, generated by the 3D structure generator CORINA with thepower of a torsional fitting technique implemented in the 3D database system UNITY. Acomparison with the original UNITY approach, using a database with about 130,000 entriesand five different pharmacophore queries, was performed. The hybrid approach scored, on anaverage, 10–20% more hits than the reference run. Moreover, specific problems withunrealistic hit geometries produced by the original approach can be excluded. In addition, theinfluence of the maximum number of ring conformations per molecule was investigated. Anoptimal number of 10 conformations per molecule is recommended.     

Measurement of loading and operations flexibility in flexible manufacturing systems: An information-theoretic approach

An information-theoretic approach is applied for measuring the flexibility in flexible manufacturing systems (FMSs). The general relation between flexibility and entropy is discussed. The entropy for a Markovian process is obtained and then applied to closed queueing network models of FMSs to discuss loading flexibility which arises from the power to regulate the frequency of the visit of a part to different work stations. The concept of operations entropy as a measure of operations flexibility, which arises from the power to choose the work station and the corresponding operations, is introduced. The operations entropy has been decomposed into entropies within and between operations and entropies within and between groups of operations. This measure has been used to determine the next operation to be performed on a part by using the principle of least reduction of flexibility.The present paper is an improved version of the paper On measurement of flexibility in flexible manufacturing systems: An information-theoretic approach, presented at the II ORSA/TIMS Special Conference on Flexible Manufacturing Systems, held at Ann Arbor in August 1986.     

Time-efficient flexible superposition of medium-sized molecules

We present an efficient algorithm for the structural alignment of medium-sized organic molecules. The algorithm has been developed for applications in 3D QSAR and in receptor modeling. The method assumes one of the molecules, the reference ligand, to be presented in the conformation that it adopts inside the receptor pocket. The second molecule, the test ligand, is considered to be flexible, and is assumed to be given in an arbitrary low-energy conformation. Ligand flexibility is modeled by decomposing the test ligand into molecular fragments, such that ring systems are completely contained in a single fragment. Conformations of fragments and torsional angles of single bonds are taken from a small finite set, which depends on the fragment and bond, respectively. The algorithm superimposes a distinguished base fragment of the test ligand onto a suitable region of the reference ligand and then attaches the remaining fragments of the test ligand in a step-by-step fashion. During this process, a scoring function is optimized that encompasses bonding terms and terms accounting for steric overlap as well as for similarity of chemical properties of both ligands. The algorithm has been implemented in the FLEXS system. To validate the quality of the produced results, we have selected a number of examples for which the mutual superposition of two ligands is experimentally given by the comparison of the binding geometries known from the crystal structures of their corresponding protein–ligand complexes. On more than two-thirds of the test examples the algorithm produces rms deviations of the predicted versus the observed conformation of the test ligand below 1.5 Å. The run time of the algorithm on a single problem instance is a few minutes on a common-day workstation. The overall goal of this research is to drastically reduce run times, while limiting the inaccuracies of the model and the computation to a tolerable level.     

On the flexibility of beta-peptides

The full conformational space was explored for an achiral and two chiral beta-peptide models: namely For-beta-Ala-NH2, For-beta-Abu-NH2, and For-beta-Aib-NH2. Stability and conformational properties of all three model systems were computed at different levels of theory: RHF/3-21G, B3LYP/6-311++G(d,p)//RHF/3-21G, B3LYP/6-311++G(d,p), MP2//B3LYP/6-311++G(d,p), CCSD//B3LYP/6-311++G(d,p), and CCSD(T)//B3LYP/6-311++G(d,p). In addition, ab initio E = E(phi, micro, psi) potential energy hypersurfaces of all three models were determined, and their topologies were analyzed to determine the inherent flexibility properties of these beta-peptide models. Fewer points were found and assigned than expected on the basis of Multidimensional Conformational Analysis (MDCA). Furthermore, it has been demonstrated, that the four-dimensional surface, E = E(phi, mu, psi), can be reduced into a three-dimensional one: E = E[phi, f(phi), psi]. This reduction of dimensionality of freedom of motion suggests that beta-peptides are less flexible than one would have thought. This agrees with experimental data published on the conformational properties of peptides composed of beta-amino acid residues.     

Three-phase solvent bar microextraction and determination of trace amounts of clenbuterol in human urine by liquid chromatography and electrospray tandem mass spectrometry

Three-phase solvent bar microextraction (TPSBME) technique is described for the quantitative determination of trace amounts of clenbuterol (CB) in urine samples using liquid chromatography (LC) and electrospray tandem mass spectrometry (ES-TMS). CB was extracted from a basified urine sample (donor phase) into the organic solvent residing in the pores of a freely moving hollow fiber and then back extracted into an acidic solution (acceptor phase) inside the lumen of the hollow fiber. The ends of the fiber were pressure-sealed. Here, forward and back extraction took place spontaneously. We studied various parameters affecting the extraction efficiency viz. type of organic solvent (octanol, nonanol and dihexyl ether) used for immobilization in the pores of the hollow fiber, i.e. extraction time (10-40 min), stirring speed (0-1000 rpm), effect of sodium chloride (0-25%, w/v) and concentration of the donor (0.25-3 M NaOH) and the acceptor (0.5-5 M formic acid) phases. After extraction, CB was analyzed by injecting the analyte enriched acceptor phase into LC combined with ES-TMS. Enrichment factor (79), repeatability (R.S.D. = 5.1%), correlation coefficient (0.9972, for the range of 0.1-4 ng mL⁻¹), detection limit (7 pg mL⁻¹) were also investigated. The present technique is compared with the reported solid phase microextraction techniques in terms of selectivity, analysis time per extraction, cost of analysis per extraction, and precision. Among all microextraction techniques reported, this technique is the most economical sample preparation/preconcentration technique to our knowledge. The method was applied for the analysis of CB in human urine.     

Probing the Interaction of the Hydroxy Group at C(4) of Lactone‐Type Inhibitors with β‐Glucosidases and β‐Galactosidases

The inhibition of the β‐glucosidases from sweet almonds and from Caldocellum saccharolyticum by the 4‐amino‐4‐deoxy lactam 11 , the 4‐deoxy lactam 12 , and the corresponding imidazoles 13 and 14 was compared to the inhibition by the hydroxy analogues 1 and 3 . Substitution of the OH group at C(4) by an amino group or by hydrogen weakened the inhibition by ΔΔG_diss = + 1.9 to + 3.1 kcal/mol. Similarly, the inhibition of the β‐galactosidase from bovine liver and from E. coli by the 4‐deoxy lactam 12 and the imidazole 14 , as compared to the one by the galacto‐configured lactam 9 and imidazole 10 , is weakened by deoxygenation at C(4) (ΔΔG_diss = + 2.6 and 4.5 kcal/mol, resp.). The effect of these substitutions on the inhibition of the C. saccharolyticum β‐glucosidase is slightly stronger than the one on the sweet almonds β‐glucosidases. The effect is also stronger on the inhibition by the imidazoles than by the lactams, and depends on the flexibility of the inhibitors. The amino and deoxy lactams 11 and 12 were prepared from the galactonolactam‐derived triflate 17 by substitution with azide and hydride, respectively, followed by hydrogenation. Azidation of the galacto‐configured imidazopyridine‐derived triflate 24 and hydrogenation gave the amino‐imidazole 13 . The deoxy lactam 20 was transformed to the manno‐ and gluco‐configured deoxy‐imidazoles 29 and 30 via the thionolactam 28 . Hydrogenolytic deprotection of 30 gave the deoxy‐imidazole 14 .     

Stir bar sorptive extraction and trace analysis of alkylphenols in water samples by thermal desorption with in tube silylation and gas chromatography-mass spectrometry

A novel method called thermal desorption (TD) with in tube silylation followed by gas chromatography-mass spectrometry (GC-MS), which is used for the determination of trace amounts of alkylphenols (APs) in river water samples, is described. APs are extracted from river water samples and concentrated by the stir bar sorptive extraction (SBSE) technique. The stir bar coated with polydimethylsiloxane (PDMS) is added to 2.0 ml water sample and stirring is carried out for 60 min at room temperature (25 degrees C) in the vial. Then, the PDMS stir bar is subjected to TD with in tube silylation followed by GC-MS. The detection limit is of the sub pg ml(-1) (ppt) level. The method shows good linearity and the correlation coefficients are higher than 0.99 for all analytes. The average recoveries of APs are higher than 90% (R.S.D.: 3.6-14.8%, n=6). This simple and sensitive analytical method may be used in the determination of trace amounts of APs in river water samples.     

Conformational study of a guaiacyl beta-O-4 lignin model compound by NMR. Examination of intramolecular hydrogen bonding interactions and conformational flexibility in solution

Intramolecular H-bonding interactions were investigated in solution for the threo and erythro diastereomeric forms of a guaiacyl beta-O-4 lignin model compound by using the NMR data obtained from hydroxyl protons. Temperature coefficients of the chemical shifts (ddelta/dT) and coupling constants (3J(HCOH)) were measured in aprotic and protic solutions: DMSO-d6, acetone-d6 and acetone-d6-water. The NMR parameters do not support the existence of strong and persistent intramolecular H-bonds that could participate in the stabilization of the guaiacyl beta-O-4 structure in solution, but instead indicate that intermolecular H-bonds to solvent predominate. 1D NOE experiments nevertheless revealed the presence of a direct chemical exchange between the hydroxyl protons, suggesting the possible existence of weak and transient intramolecular H-bonding interactions. The conformational flexibility of the threo structure was also investigated in acetone solution from the measurement of long-range 1H, 1H and 1H, 13C coupling constants and from NOESY experiments. The NMR data are not consistent with any single conformation, indicating that different conformers co-exist in solution. The experimental results support the conformational flexibility predicted by molecular dynamics simulations performed in a previous study. Finally, both experimental and theoretical approaches indicate that weak intramolecular H-bonds can exist transiently in solution, breaking and reforming as the beta-O-4 molecule undergoes conformational interconversion, but cannot be invoked as possible means of conferring rigidity to the beta-O-4 structure.