Application of Ionic Liquids in Pot-in-Pot Reactions

Pot-in-pot reactions are designed such that two reaction media (solvents, catalysts and reagents) are isolated from each other by a polymeric membrane similar to matryoshka dolls (Russian nesting dolls). The first reaction is allowed to progress to completion before triggering the second reaction in which all necessary solvents, reactants, or catalysts are placed except for the starting reagent for the target reaction. With the appropriate trigger, in most cases unidirectional flux, the product of the first reaction is introduced to the second medium allowing a second transformation in the same glass reaction potalbeit separated by a polymeric membrane. The basis of these reaction systems is the controlled selective flux of one reagent over the other components of the first reaction while maintaining steady-state catalyst concentration in the first pot. The use of ionic liquids as tools to control chemical potential across the polymeric membranes making the first pot is discussed based on standard diffusion modelsFickian and Payne's models. Besides chemical potential, use of ionic liquids as delivery agent for a small amount of a solvent that slightly swells the polymeric membrane, hence increasing flux, is highlighted. This review highlights the critical role ionic liquids play in site-isolation of multiple catalyzed reactions in a standard pot-in-pot reaction

D3R grand challenge 2015: Evaluation of protein–ligand pose and affinity predictions

The Drug Design Data Resource (D3R) ran Grand Challenge 2015 between September 2015 and February 2016. Two targets served as the framework to test community docking and scoring methods: (1) HSP90, donated by AbbVie and the Community Structure Activity Resource (CSAR), and (2) MAP4K4, donated by Genentech. The challenges for both target datasets were conducted in two stages, with the first stage testing pose predictions and the capacity to rank compounds by affinity with minimal structural data; and the second stage testing methods for ranking compounds with knowledge of at least a subset of the ligand-protein poses. An additional sub-challenge provided small groups of chemically similar HSP90 compounds amenable to alchemical calculations of relative binding free energy. Unlike previous blinded Challenges, we did not provide cognate receptors or receptors prepared with hydrogens and likewise did not require a specified crystal structure to be used for pose or affinity prediction in Stage 1. Given the freedom to select from over 200 crystal structures of HSP90 in the PDB, participants employed workflows that tested not only core docking and scoring technologies, but also methods for addressing water-mediated ligand-protein interactions, binding pocket flexibility, and the optimal selection of protein structures for use in docking calculations. Nearly 40 participating groups submitted over 350 prediction sets for Grand Challenge 2015. This overview describes the datasets and the organization of the challenge components, summarizes the results across all submitted predictions, and considers broad conclusions that may be drawn from this collaborative community endeavor

Insights into mechanism of anticancer activity of pentacyclic oxindole alkaloids of Uncaria tomentosa by means of a computational reverse virtual screening and molecular docking approach

Alkaloid-rich extract from Uncaria tomentosa (eng. Cat’s claw) has been reported to cause apoptosis in vitro in cancer lines. Oxindole pentacyclic alkaloids of the plant are responsible for this effect, yet their biological mechanism of action is not fully understood. In this work the set of these alkaloids underwent an extensive theoretical study with reverse virtual screening and molecular docking methods implemented in AutoDock, AutoDock Vina and Molegro Virtual Docker. The obtained results from these computational methods indicate that inhibition of dihydrofolate reductase and MDM2 may be responsible for the biological activity of the alkaloids. The docking results also show that alkaloids can interact with Dvl-2, Akt-2 and leukotriene A4 hydrolase. The reverse virtual screening and molecular docking are valuable tools to aid identification of protein targets for bioactive hit molecules and could guide the design of in-depth biochemical activity tests and utilization of these alkaloids in anticancer drug development.Peer reviewe

Exploring the Catalytic Mechanism of Alkanesulfonate Monooxygenase Using Molecular Dynamics

The complex mechanistic properties of alkanesulfonate monooxygenase (SsuD) provide a particular challenge for identifying catalytically relevant amino acids. In response, a joint computational and experimental study was conducted to further elucidate the SsuD mechanism. Extensive unbiased molecular dynamics (MD) simulations were performed for six SsuD systems: (1) substrate-free, (2) bound with FMNH2, (3) bound with a C4a-peroxyflavin intermediate (FMNOO(-)), (4) bound with octanesulfonate (OCS), (5) co-bound with FMNH2 and OCS, and (6) co-bound with FMNOO(-) and OCS. A previous theoretical study suggested that salt bridges between Arg297 and Glu20 or Asp111 initiated conformational changes critical for catalysis. However, our MD simulations and steady-state kinetic experiments did not corroborate this result. Similar kcat/Km values for both the E20A and D111A SsuD variants to wild-type SsuD suggest that the salt bridges are not critical to the desulfonation mechanism. Instead, the predicted role of Arg297 is to favorably interact with the phosphate group of the reduced flavin. Concomitantly, Arg226 functioned as a "protection" group shielding FMNOO(-) from bulk solvent and was more pronounced when both FMNOO(-) and OCS were bound. The stabilization of FMNOO(-) through electrostatic interactions with Arg226 would properly position the C4a peroxy group for the proposed nucleophilic attack on the sulfur of octanesulfonate