A comparative assessment of octanol-water partitioning and distribution constant estimation methods for perfluoroalkyl carboxylates and sulfonates

New experimental data is available in the literature regarding the octanol-water distribution behavior of representative straight chain perfluoroalkyl carboxylate (PFCA) and sulfonate (PFSA) congeners. The current study provides the first investigation into the predictive ability of various software programs for estimating the corresponding octanol-water partitioning (log P) and distribution (log D) constants of PFCAs and PFSAs. Wide predictive variation was found within and between the various methods. Several programs were able to accurately estimate the log P/D fragmental contributions of a -CF~2~- group for PFCAs, as well as the associated Gibbs free energies for partitioning into octanol from water due to the hydrophobic character of the perfluoroalkyl chain (Δ~hydrophobic~G~ow~). Only the SPARC log D method accurately predicted the electrostatic contributions of the carboxylate head group (Δ~electrostatic~G~ow~) towards octanol-water partitioning for PFCAs. Similar log D values and organic carbon normalized sediment-water partitioning coefficients (K~oc~) for PFCAs and PFSAs having equivalent perfluoroalkyl chain lengths suggests potentially equivalent Δ~electrostatic~G~ow~ and Δ~hydrophobic~G~ow~ contributions towards lipophilic partitioning for these two contaminant classes, regardless of head group identity. In contrast, there are potentially different Δ~electrostatic~G~ow~ and Δ~hydrophobic~G~ow~ contributions towards proteinophilic partitioning

Uncertainty Quantification Using Neural Networks for Molecular Property Prediction

Uncertainty quantification (UQ) is an important component of molecular property prediction, particularly for drug discovery applications where model predictions direct experimental design and where unanticipated imprecision wastes valuable time and resources. The need for UQ is especially acute for neural models, which are becoming increasingly standard yet are challenging to interpret. While several approaches to UQ have been proposed in the literature, there is no clear consensus on the comparative performance of these models. In this paper, we study this question in the context of regression tasks. We systematically evaluate several methods on five benchmark datasets using multiple complementary performance metrics. Our experiments show that none of the methods we tested is unequivocally superior to all others, and none produces a particularly reliable ranking of errors across multiple datasets. While we believe these results show that existing UQ methods are not sufficient for all common use-cases and demonstrate the benefits of further research, we conclude with a practical recommendation as to which existing techniques seem to perform well relative to others

Discovery of TUG-770: a highly potent free fatty acid receptor 1 (FFA1/GPR40) agonist for treatment of type 2 diabetes

Free fatty acid receptor 1 (FFA1 or GPR40) enhances glucose-stimulated insulin secretion from pancreatic β-cells and currently attracts high interest as a new target for the treatment of type 2 diabetes. We here report the discovery of a highly potent FFA1 agonist with favorable physicochemical and pharmacokinetic properties. The compound efficiently normalizes glucose tolerance in diet-induced obese mice, an effect that is fully sustained after 29 days of chronic dosing

Molecular similarity of MDR inhibitors

Everyone is free to re-use the published material if proper accreditation/citation of the original publication is given. http://creativecommons.org/licences/by/3.0/The molecular similarity of multidrug resistance (MDR) inhibitors was evaluated using the point centred atom charge approach in an attempt to find some common features of structurally unrelated inhibitors. A series of inhibitors of bacterial MDR were studied and there is a high similarity between these in terms of their shape, presence and orientation of aromatic ring moieties. A comparison of the lipophilic properties of these molecules has also been conducted suggesting that this factor is important in MDR inhibition.Peer reviewe

2-Oxoesters: A Novel Class of Potent and Selective Inhibitors of Cytosolic Group IVA Phospholipase A2.

Cytosolic phospholipase A2 (GIVA cPLA2) is the only PLA2 that exhibits a marked preference for hydrolysis of arachidonic acid containing phospholipid substrates releasing free arachidonic acid and lysophospholipids and giving rise to the generation of diverse lipid mediators involved in inflammatory conditions. Thus, the development of potent and selective GIVA cPLA2 inhibitors is of great importance. We have developed a novel class of such inhibitors based on the 2-oxoester functionality. This functionality in combination with a long aliphatic chain or a chain carrying an appropriate aromatic system, such as the biphenyl system, and a free carboxyl group leads to highly potent and selective GIVA cPLA2 inhibitors (X I(50) values 0.00007-0.00008) and docking studies aid in understanding this selectivity. A methyl 2-oxoester, with a short chain carrying a naphthalene ring, was found to preferentially inhibit the other major intracellular PLA2, the calcium-independent PLA2. In RAW264.7 macrophages, treatment with the most potent 2-oxoester GIVA cPLA2 inhibitor resulted in over 50% decrease in KLA-elicited prostaglandin D2 production. The novel, highly potent and selective GIVA cPLA2 inhibitors provide excellent tools for the study of the role of the enzyme and could contribute to the development of novel therapeutic agents for the treatment of inflammatory diseases

Planning Graph Heuristics for Belief Space Search

Some recent works in conditional planning have proposed reachability heuristics to improve planner scalability, but many lack a formal description of the properties of their distance estimates. To place previous work in context and extend work on heuristics for conditional planning, we provide a formal basis for distance estimates between belief states. We give a definition for the distance between belief states that relies on aggregating underlying state distance measures. We give several techniques to aggregate state distances and their associated properties. Many existing heuristics exhibit a subset of the properties, but in order to provide a standardized comparison we present several generalizations of planning graph heuristics that are used in a single planner. We compliment our belief state distance estimate framework by also investigating efficient planning graph data structures that incorporate BDDs to compute the most effective heuristics. We developed two planners to serve as test-beds for our investigation. The first, CAltAlt, is a conformant regression planner that uses A* search. The second, POND, is a conditional progression planner that uses AO* search. We show the relative effectiveness of our heuristic techniques within these planners. We also compare the performance of these planners with several state of the art approaches in conditional planning

On the ordeal of quinolone preparation via cyclisation of aryl-enamines; synthesis and structure of ethyl 6-methyl-7-iodo-4-(3-iodo-4-methylphenoxy)-quinoline-3-carboxylate

Recent studies directed to the design of compounds targeting the bc(1) protein complex of Plasmodium falciparum, the parasite responsible for most lethal cases of malaria, identified quinolones (4-oxo-quinolines) with low nanomolar inhibitory activity against both the enzyme and infected erythrocytes. The 4-oxo-quinoline 3-ester chemotype emerged as a possible source of potent bc(1) inhibitors, prompting us to expand the library of available analogs for SAR studies and subsequent lead optimization. We now report the synthesis and structural characterization of unexpected ethyl 6-methyl-7-iodo-4-(3-iodo-4-methylphenoxy)quinoline-3-carboxylate, a 4-aryloxy-quinoline 3-ester formed during attempted preparation of 6-methyl-7-iodo-4-oxo-quinoline-3-carboxylate (4-oxo-quinoline 3-ester). We propose that the 4-aryloxy-quinoline 3-ester derives from 6-methyl-7-iodo-4-hydroxy-quinoline-3-carboxylate (4-hydroxy-quinoline 3-ester), the enol form of 6-methyl-7-iodo-4-oxo-quinoline-3-carboxylate. Formation of the 4-aryloxy-quinoline 3-ester confirms the impact of quinolone/hydroxyquinoline tautomerism, both on the efficiency of synthetic routes to quinolones and on pharmacologic profiles. Tautomers exhibit different cLogP values and interact differently with the enzyme active site. A structural investigation of 6-methyl-7-iodo-4-oxo-quinoline-3-carboxylate and 6-methyl-7-iodo-4-hydroxy-quinoline-3-carboxylate, using matrix isolation coupled to FTIR spectroscopy and theoretical calculations, revealed that the lowest energy conformers of 6-methyl-7-iodo-4-hydroxy-quinoline-3-carboxylate, lower in energy than their most stable 4-oxo-quinoline tautomer by about 27 kJ mol(-1), are solely present in the matrix, while the most stable 4-oxo-quinoline tautomer is solely present in the crystalline phase.Fundacao para a Ciencia e Tecnologia (FCT - Portugal) [UID/Multi/04326/2013]; QREN-COMPETE-UE; CCMAR; FCT [SFRH/BD/81821/2011, RECI/BBB-BQB/0230/2012, UI0313/QUI/2013, UID/FIS/04564/2016]; FEDER/COMPETE-UE; [PTDC/QEQ-QFI/3284/2014 - POCI-01-0145-FEDER-016617]info:eu-repo/semantics/publishedVersio

Partitioning of Poly(amidoamine) Dendrimers between n-Octanol and Water

Dendritic nanomaterials are emerging as key building blocks for a variety of nanoscale materials and technologies. Poly(amidoamine) (PAMAM) dendrimers were the first class of dendritic nanomaterials to be commercialized. Despite numerous investigations, the environmental fate, transport, and toxicity of PAMAM dendrimers is still not well understood. As a first step toward the characterization of the environmental behavior of dendrimers in aquatic systems, we measured the octanol−water partition coefficients (logK_(ow)) of a homologous series of PAMAM dendrimers as a function of dendrimer generation (size), terminal group and core chemistry. We find that the logKow of PAMAM dendrimers depend primarily on their size and terminal group chemistry. For G1-G5 PAMAM dendrimers with terminal NH_2 groups, the negative values of their logK_(ow) indicate that they prefer to remain in the water phase. Conversely, the formation of stable emulsions at the octanol−water (O/W) interface in the presence of G6-NH_2 and G8-NH_2 PAMAM dendrimers suggest they prefer to partition at the O/W interface. In all cases, published studies of the cytotoxicity of Gx-NH_2 PAMAM dendrimers show they strongly interact with the lipid bilayers of cells. These results suggest that the logKow of a PAMAM dendrimer may not be a good predictor of its affinity with natural organic media such as the lipid bilayers of cell membranes