Formic Acid,a Ubiquitous but Overlooked Component of the Early Earth Atmosphere

Terrestrial volcanism has been one of the dominant geological forces shaping our planet since its earliest existence. Its associated phenomena, like atmospheric lightning and hydrothermal activity, provide a rich energy reservoir for chemical syntheses. Based on our laboratory simulations, we propose that on the early Earth volcanic activity inevitably led to a remarkable production of formic acid through various independent reaction channels. Large-scale availability of atmospheric formic acid supports the idea of the high-temperature accumulation of formamide in this primordial environment.     

Plane rotations and Hamilton—Dirac mechanics

Canonical formalism for SO(2) is developed. This group can be seen as a toy model of the Hamilton-Dirac mechanics with constraints. The Lagrangian and Hamiltonian are explicitly constructed and their physical interpretations are given. The Euler-Lagrange and Hamiltonian canonical equations coincide with the Lie equations. It is shown that the constraints satisfy CCR. Consistency of the constraints is checked. Presented at the International Colloquium “Integrable Systems and Quantum Symmetries”, Prague, 16–18 June 2005.     

Exploring fragment spaces under multiple physicochemical constraints

We present a new algorithm for the enumeration of chemical fragment spaces under constraints. Fragment spaces consist of a set of molecular fragments and a set of rules that specifies how fragments can be combined. Although fragment spaces typically cover an infinite number of molecules, they can be enumerated in case that a physicochemical profile of the requested compounds is given. By using min-max ranges for a number of corresponding properties, our algorithm is able to enumerate all molecules which obey these properties. To speed up the calculation, the given ranges are used directly during the build-up process to guide the selection of fragments. Furthermore, a topology based fragment filter is used to skip most of the redundant fragment combinations. We applied the algorithm to 40 different target classes. For each of these, we generated tailored fragment spaces from sets of known inhibitors and additionally derived ranges for several physicochemical properties. We characterized the target-specific fragment spaces and were able to enumerate the complete chemical subspaces for most of the targets.     

Solvolytic reactivity of pyridinium ions

The leaving group abilities of pyridine, 4‐methylpyridine, and 4‐chloropyridine in S_N1 solvolytic reactions have been determined by analyzing the rate constants of X,Y‐substituted benzhydrylpyridinium salts obtained in various solvents. By applying the linear free energy relationship equation, log k = s_f (E_f + N_f), the nucleofuge specific parameters of 4‐substituted pyridine have been extracted. Because of solvation in the reactant ground state, the reactivity (nucleofugality, N_f) of a given pyridine decreases as the polarity of the solvent increases. High slope parameters (s_f > 1) may be due to the spread of the energy levels of the benzhydrylium ion/pyridine pair intermediates in comparison to benzhydrylium ion/chloride pairs (s_f ≈ 1). Because of slow heterolysis step of pyridinium salts in various solvents, some are stable under normal conditions. Copyright © 2015 John Wiley & Sons, Ltd.     

Design and synthesis of an inositol phosphate analog based on computational docking studies

A virtual library of 54 inositol analog mimics of In(1,4,5)P₃ has been docked, scored, and ranked within the binding site of human inositol 1,4,5-trisphosphate 3-kinase A (IP₃-3KA). Chemical synthesis of the best scoring structure that also met distance criteria for 3′-OH to -P in phosphate has been attempted along with the synthesis of (1S,2R,3S,4S)-3-fluoro-2,4-dihydroxycyclohexanecarboxylic acid as an inositol analog, useful for non-invasive visualization and quantitation of IP₃-3KA enzymatic activity.     

Second-generation de novo design: a view from a medicinal chemist perspective

For computational de novo design, a general retrospective validation work is a very challenging task. Here we propose a comprehensive workflow to de novo design driven by the needs of computational and medicinal chemists and, at the same time, we propose a general validation scheme for this technique. The study was conducted combining a suite of already published programs developed within the framework of the NovoBench project, which involved three different pharmaceutical companies and four groups of developers. Based on 188 PDB protein–ligand complexes with diverse functions, the study involved the ligand reconstruction by means of a fragment-based de-novo design approach. The structure-based de novo search engine FlexNovo showed in five out of eight total cases the ability to reconstruct native ligands and to rank them in four cases out of five within the first five candidates. The generated structures were ranked according to their synthetic accessibilities evaluated by the program SYLVIA. This investigation showed that the final candidate molecules have about the same synthetic complexity as the respective reference ligands. Furthermore, the plausibility of being true actives was assessed through literature searches. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.

On the binding energy values and excited states of some a ≧ 10 hypernuclei

New binding energy values for the hypernuclei ¹⁰_ΛBe and ¹⁴_ΛC have been determined while those of ¹³_ΛC and ¹⁵_ΛN have been reassessed. The existence of a narrow particle-unstable state of ¹²_gLC is affirmed but the previously quoted evidence for the existence of a narrow state of the ¹⁴_ΛN hypernucleus is shown to be invalid.     

Molecular topological index: An application in the QSAR study of toxicity of alcohols

An application of the molecular topological index, adapted for heterosystems, in the QSAR study of toxicity of alkyl alcohols on fathead minnows (Pimephates promelas) is examined. The obtained QSAR model is comparable to models based on the Wiener number and the connectivity index.