Predicting the affinity of Farnesoid X Receptor ligands through a hierarchical ranking protocol: a D3R Grand Challenge 2 case study

The Drug Design Data Resource (D3R) Grand Challenges are blind contests organized to assess the state-of-the-art methods accuracy in predicting binding modes and relative binding free energies of experimentally validated ligands for a given target. The second stage of the D3R Grand Challenge 2 (GC2) was focused on ranking 102 compounds according to their predicted affinity for Farnesoid X Receptor. In this task, our workflow was ranked 5th out of the 77 submissions in the structure-based category. Our strategy consisted in (1) a combination of molecular docking using AutoDock 4.2 and manual edition of available structures for binding poses generation using SeeSAR, (2) the use of HYDE scoring for pose selection, and (3) a hierarchical ranking using HYDE and MM/GBSA. In this report, we detail our pose generation and ligands ranking protocols and provide guidelines to be used in a prospective computer aided drug design program.     

Alcohol uncaging with fluorescence reporting: evaluation of o-acetoxyphenyl methyloxazolone precursors

This paper evaluates a series of photolabile protecting groups with built-in fluorescence reporting. They rely on readily available o-acetoxyphenyl methyloxazolones as activated precursors. Alcohol substrates are easily caged. The resulting photoactivable esters exhibit large one- and two-photon uncaging cross sections. The alcohol substrates are quantitatively released in a 1:1 molar ratio with a strongly fluorescent coumarin coproduct that serves as a reporter to quantify substrate delivery.     

Phenylenediamine catalysis of "click glycosylations" in water: practical and direct access to unprotected neoglycoconjugates

Phenylenediamine-catalyzed click chemistry leads to the efficient, practical, and column-free preparation of neoglycoconjugates from unprotected glucosyl azide, in pure water when aglycon solubility permits.     

A Julia olefination approach to the synthesis of functionalized enol ethers and their transformation into carbohydrate-derived spiroketals

A synthesis of spiroketals from carbohydrate lactones is reported. A modified Julia olefination is used to synthesize trisubstituted and highly functionalized exo-glycals, which were subsequently transformed into spiroketals under acidic conditions.     

Multiple homo- and hetero-functionalizations of alpha-cyclodextrin through oriented deprotections

Introduction of one or more functions on a cyclodextrin in a regioselective manner is a complex task. The discovery of a blueprint strategy involving regioselective deprotection reactions of fully protected cyclodextrins, instead of functionalization of native cyclodextrins, allowed us to propose an efficient alternative to reach this goal. In this paper, we have applied previously delineated strategies, based on steric decompression, to duplicate our deprotection reaction, using a combination of mono- or di-deprotections to access cyclodextrins with two, three and five points of attachment for one, two or three different new functions. The patterns of multi-functionalization delineated here are not accessible by any other methods. Indeed, it is the first time ever a cyclodextrin bearing four different groups is synthesized in a completely controlled manner. This work paves the way to the use of cyclodextrins as multi-functional macrocyclic scaffolds, a use they have long been meant for, but lack of reliable functionalization methods hindered this development.     

Evaluation of a new matrix-free laser desorption/ionization method through statistic studies: comparison of the DIAMS (desorption/ionization on self-assembled monolayer surface) method with the MALDI and TGFA-LDI techniques

This work demonstrates that the desorption/ionization on self-assembled monolayer surface (DIAMS) mass spectrometry, a recent matrix-free laser desorption/ionization (LDI) method based on an organic target plate, is as statistically repeatable and reproducible as matrix assisted laser desorption ionization (MALDI) and thin gold film-assisted laser desorption/ionization (TGFA-LDI) mass spectrometries. On lipophilic DIAMS of target plates with a mixture of glycerides, repeatability/reproducibility has been estimated at 15 and 30% and the relative detection limit has been evaluated at 0.3 and 3 pmol, with and without NaI respectively. Salicylic acid and its d(6)-isomer analysis confirm the applicability of the DIAMS method in the detection of compounds of low molecular weight.     

Separation of casein micelles from whey proteins by high shear microfiltration of skim milk using rotating ceramic membranes and organic membranes in a rotating disk module

This paper investigates the microfiltration of skim milk in order to separate caseins micelles from two whey proteins, α-lactalbumin (α-La) and β-lactoglobulin (β-Lg), using a modified dynamic filtration pilot (MSD) consisting in 6 ceramic 9-cm diameter membrane disks of 0.2 μm pores, rotating around a shaft inside cylindrical housing. A comparison was made with another dynamic filtration module consisting in a disk rotating near a fixed PVDF 15.5 cm diameter membrane with 0.15 μm pores. Maximum permeate fluxes were 120 L h⁻¹ m⁻² with the MSD module at 1930 rpm and at 40 °C, and 210 L h⁻¹ m⁻² at 2500 rpm and 45 °C, with the rotating disk module. Casein rejection was around 99% at high speed for both membranes. α-La transmission decreased with increasing transmembrane pressure (TMP) from 75% to 60% for ceramic membranes and from 25% to 10% for the PVDF one. β-Lg transmissions were lower, ranging from 23% to 15% for ceramic membranes and from 20% to 5% for the PVDF one. In a concentration test with the PVDF membrane at 2000 rpm, the flux decayed from 200 L h⁻¹ m⁻² at initial concentration to 80 L h⁻¹ m⁻² at VRR = 3.2 and 22.1% of the initial α-La mass was recovered in the permeate, against 8.1% for β-Lg. Permeate fluxes in the mass transfer limited regime (J_lim) of the MSD and rotating disk module operated at various speeds were well correlated by the equation J_lim = 17.13 V_av where V_av denoted the disk azimuthal velocity averaged over the membrane area. Measurements of J_lim, taken from Ref. [G. Samuelsson, P. Dejlmek, G. Tragardh, M. Paulsson, Minimizing whey protein retention in crossflow microfiltration of skim milk. Int. Dairy J. 7 (1997) 237–242] during MF of skim milk using tubular ceramic membranes at velocities from 1.5 to 8 m s⁻¹ with permeate co-current recirculation were found to obey the same correlation.     

Reversibly permeable nanomembranes of polymeric microcapsules

Polymeric nanometer-thick membranes or nanomembranes possessing photocontrollable permeability are presented. Microcapsules are used as membrane model systems, while gold nanoparticle aggregates are used as active absorption centers. Upon laser light illumination the membranes change permeability reversibly because nanoparticles transiently affect the nearby polymeric network. Nanomembranes reseal to their impermeable state when the laser is switched off. This presents a novel and simple way of reversible permeability control of interest to intracellular signaling and membranes.     

Synthesis of Optically Active Polystyrene Catalyzed by Monophosphine Pd Complexes

Cationic Pd^II monophosphine complexes derived from α‐ and β‐cyclodextrins (CDs) promote the homopolymerization of styrene under carbon monoxide pressure. Although reversible CO coordination takes place under catalytic conditions according to ¹³C NMR studies with ¹³C‐enriched CO, both complexes catalyze the formation of CO‐free styrene polymers. These macromolecules display optical activity as a result of the presence of stereoregular sequences within the overall atactic polymer.     

On the influence of wavy riblets on the slip behaviour of viscous fluids

In this work, we use the homogenization theory to investigate the capability of wavy riblet patterns to influence the behaviour of a viscous flow near a ribbed boundary. Starting from perfect slip conditions on the wall, we show that periodic oscillations of wavy riblets in the lateral direction may induce a friction effect in the direction of the flow, contrary to what happens with straight riblets. Finally, we illustrate this effect numerically by simulating riblet profiles that are widely used in experimental studies: the V-shape, U-shape, and blade riblets.