A new approach to predict the biological activity of molecules based on similarity of their interaction fields and the logP and logD values: application to auxins

The activity of a biological compound is dependent both on specific binding to a target receptor and its ADME (Absorption, Distribution, Metabolism, Excretion) properties. A challenge to predict biological activity is to consider both contributions simultaneously in deriving quantitative models. We present a novel approach to derive QSAR models combining similarity analysis of molecular interaction fields (MIFs) with prediction of logP and/or logD. This new classification method is applied to a set of about 100 compounds related to the auxin plant hormone. The classification based on similarity of their interaction fields is more successful for the indole than the phenoxy compounds. The classification of the phenoxy compounds is however improved by taking into account the influence of the logP and/or the logD values on biological activity. With the new combined method, the majority (8 out of 10) of the previously misclassified derivatives of phenoxy acetic acid are classified in accord with their bioassays. The recently determined crystal structure of the auxin-binding protein 1 (ABP1) enabled validation of our approach. The results of docking a few auxin related compounds with different biological activity to ABP1 correlate well with the classification based on similarity of MIFs only. Biological activity is, however, better predicted by a combined similarity of MIFs + logP/logD approach.     

Ringerweiterung unter Lactonisierung von methylierten 1-(3′-Hydroxypropyl)-2-oxocyclododecan-1-carbonitrilen

Ring Enlargement by Lactonization of Methylated 1-(3′-Hydroxypropy1)-2-oxocyclododecane-1-carbonitriles The title compounds were prepared by Michael reaction of 2-oxocyclododecane-1-carbonitrile ( 1 ) and acrylaldehyde and its derivatives followed by NaBH₄ reduction or methylation of the aldehyde group with [(CH₃)₂Ti(i-PrO)₂] (Scheme 1). In all cases, the ring enlargement was performed with Bu₄NF/THF to give different methylated derivatives of 12-cyano-15-pentadecanolide ( 13 ) in 95–99% yield. The Yields of the rearrangement products are not dependent on the positions and numbers of the CH₃ groups in the side chain of 3 . The lactonization reaction is of unremarkable stereoselectivity.     

Synthese von 12-Cyano-15-hexadecanolid durch Ringerweiterung von 1-(3′-Hydroxybutyl)-2-oxocyclododecan-1-carbonitril

Synthesis of 12-Cyano-15-hexadecanolide by Ring Enlargement of 1-(3′-Hydroxybutyl)-2-oxocyclododecane-1-carbonitrile In the presence of Bu₄NF, 2-oxocyclododecane-1-carbonitrile ( 1 ) reacted with acrylaldehyde to form the corresponding aldehyde 2 which was methylated, e.g. with CH₃ Ti[OCH(CH₃)₂]₃. The resulting 1-(3′-hydroxybutyl)-2-oxocyclododecane-1-carbonitrile ( 5 ) was converted to 12-cyano-15-hexadecanolide ( 6 ) in nearly quantitative yield under the influence of Bu₄NF.     

Anisotropic memory effects in confined colloidal diffusion

The motion of an optically trapped sphere constrained by the vicinity of a wall is investigated at times where hydrodynamic memory is significant. First, we quantify, in bulk, the influence of confinement arising from the trapping potential on the sphere's velocity autocorrelation function C(t). Next, we study the splitting of C(t) into C_{parallel}(t) and C_{perpendicular}(t), when the sphere is approached towards a surface. Thereby, we monitor the crossover from a slow t{-3/2} long-time tail, away from the wall, to a faster t{-5/2} decay, due to the subtle interplay between hydrodynamic backflow and wall effects. Finally, we discuss the resulting asymmetric time-dependent diffusion coefficients.     

Chromatography,mass spectrometry,and molecular modeling studies on ammodytoxins

The ammodytoxins (Atxs) are neurotoxic phospholipases which occur in Vipera ammodytes ammodytes (Vaa) snake venom. There are three Atx isoforms, A, B, and C, which differ in only five amino acid positions at the C-terminus but differ substantially in their toxicity. The objective of this study was to establish an analytical method for unambiguous identification of all three isoforms and to use the method to assess a procedure for purification of the most toxic phospholipase, AtxA, from the venom. Isolation procedure for AtxA consisted of isolation of Atx-cross-reactive material (proteins recognized by anti-Atx antibodies), by use of an affinity column, then cation exchange on CIM (Convective Interaction Media) disks. The purification procedure was monitored by means of reversed-phase chromatography (RPC) and mass spectrometry (MS). Although previous cation exchange of the pure isoforms enabled separate elution of AtxA from B and C, separation of AtxA from Atxs mixture was not accomplished. RPC was not able to separate the Atx isoforms, whereas an MS based approach proved to be more powerful. Peptides resulting from tryptic digestion of Atxs which enable differentiation between the three isoforms were successfully detected and their sequences were confirmed by post-source decay (PSD) fragmentation. Separation of Atx isoforms by ion-exchange chromatography is most presumably prevented by Atxs heterodimer formation. The tendency of Atxs to form homodimers and heterodimers of similar stability was confirmed by molecular modeling.     

A note on CIP varieties

It is proved that every variety satisfying the Congruence Intersection Property (CIP) is Abelian. In addition, a CM Abelian variety has the CIP if and only if it has a constant term operation. Finally, a CM variety is Abelian if and only if it has the weak CIP. Received October 8, 1998; accepted in final form January 5, 1999.     

On the lattice of weak congruence relations

We consider the setC _w (A) of weak congruences on an algebraA, i.e. of all symmetric and transitive subalgebras ofA ×A. (Some other generalizations of compatible relations were given in [2] and [6]).C _w (A) coincides with the set of all congruences on all subalgebras ofA.We prove here that (^iC _w(A),) is an algebraic lattice having as a sublattice the lattice of all congruences onA, and as a retract the lattice of all its subalgebras. In the second part we give necessary and sufficient conditions (one is the CEP) for modularity as well as for distributivity of the lattice of weak congruences.Presented by H. P. Gumm.     

The basic feasible functionals in computable analysis

We give a correspondence between two notions of complexity for real functions: poly-time computability according to Ko and a notion that arises naturally when one considers the application of Mehlhorn's class of the basic feasible functionals to computable analysis. We show that both notions define the same set of polynomial-time computable real functions.     

Synthesis of trans-Non-4-EN-2-Ynoic Acid

The synthesis of the title compound has been achieved from 1 -methoxybutenyne in 77% yield in three steps. A reaction mechanism is given to explain exclusive formation of 4,5-trans-configuration.