Significance
mAbs are increasingly being used for treatment of chronic diseases wherein the subcutaneous delivery route is preferred to enable self-administration and at-home use. To deliver high doses (several hundred milligrams) through a small volume (∼1 mL) into the subcutaneous space, mAb solutions need to have low viscosity. Concomitantly, acceptable chemical stability is required for adequate shelf life, and normal in vivo clearance is needed for less frequent dosing. We propose in silico tools that provide rapid assessment of atypical behavior of mAbs (high viscosity, chemical degradation, and fast plasma clearance), which are simply predicted from sequence and/or structure-derived parameters. Such analysis will greatly improve the probability of success to move mAb-based therapeutics efficiently into clinical development and ultimately benefit patients.
Bitumen flotation hydrodynamics in water‐based oil sand extraction is critically reviewed by comparing aeration of oil sand slurries with mineral flotation. The role of the two‐stage particle‐bubble attachment model in flotation is emphasized as a means to accelerate bitumen flotation recovery. It involves the generation of micro/nanobubbles and their frosting on hydrophobic bitumen droplets, followed by their attachment to a flotation‐size bubble via its coalescence with the nanobubbles frosted on the bitumen. Nanobubble generation by hydrodynamic cavitation demonstrates that the size of nanobubbles can be reduced, and the number of nanobubbles increased by fast liquid flow, intensified agitation, high dissolved gas content and surfactant concentration. The mechanism of pre‐existing gas nuclei in enhancing nanobubble generation by cavitation is utilized to produce a large volume of stabilized nanobubbles for practical flotation, by continuously recirculating the stream through a gas saturation tank or a cavitation tube. The aeration of oil sand slurries in hydrotransport pipelines is analyzed based on its similarity to dissolved air flotation. Bitumen extraction recovery increased significantly with the presence of nanobubbles in the system. The role of improved flotation hydrodynamics in bitumen recovery is briefly discussed in terms of the Suncor operation using flotation columns to process oil sand middling streams. Future research should be directed at understanding bitumen flotation kinetics, optimizing size ranges of nanobubbles for maximized flotation recovery, minimizing wearing of cavitation tubes in industrial operations, and intensifying the role of in‐situ nanobubble nucleation on hydrophobic particles/bitumen droplets in flotation, especially for bitumen extraction from underperforming oil sands.
The discovery and optimization of potency and metabolic stability of a novel class of dihyroxyphenylisoindoline amides as Hsp90 inhibitors are presented. Optimization of a screening hit using structure-based design and modification of log D and chemical structural features led to the identification of a class of orally bioavailable non-quinone-containing Hsp90 inhibitors. This class is exemplified by 14 and 15, which possess improved cell potency and pharmacokinetic profiles compared with the original screening hit.
An unprecedented amount of parallel synthesis information was accumulated within Pfizer over the past 12 years. This information was captured by an informatics tool known as PGVL (Pfizer Global Virtual Library). PGVL was used for many aspects of drug discovery including automated reactant mining and reaction product formation to build a synthetically feasible virtual compound collection. In this report, PGVL is discussed in detail. The chemistry information within PGVL has been used to extract synthesis and design information using an intuitive desktop Graphic User Interface, PGVL Hub. Several real-case examples of PGVL are also presented.
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