Ion Mobility-Mass Spectrometry Strategies to Elucidate the Anhydrous Structure of Noncovalent Guest/Host Complexes.

Structural mass spectrometry (MS) techniques are fast and sensitive analytical methods to identify noncovalent guest/host complexation phenomena for desirable solution-phase properties. Current MS-based studies on guest/host complexes of drug and drug-like molecules are sparse, and there is limited guidance on how to interpret MS information in the context of host nanoencapsulation and inclusion. Here, we use structural MS strategies, combining energy-resolved MS (ERMS), ion mobility-MS (IM-MS), and computational modeling, to characterize 14 chemically distinct drug and drug-like compounds for their propensity to form guest/host complexes with the widely used excipient, beta-cyclodextrin (βCD).

Noncovalent Host-Guest Complexes of Artemisinin with α-, β-, and γ- Cyclodextrin Examined by Structural Mass Spectrometry Strategies.

Cyclodextrins (CDs) are a family of macrocyclic oligosaccharides with amphiphilic properties, which can improve the stability, solubility, and bioavailability of therapeutic compounds. There has been growing interest in the advancement of efficient and reliable analytical methods that assist with elucidating CD host-guest drug complexation. In this study, we investigate the noncovalent ion complexes formed between naturally occurring dextrins (αCD, βCD, γCD, and maltohexaose) with the poorly water-soluble antimalarial drug, artemisinin, using a combination of ion mobility-mass spectrometry (IM-MS), tandem MS/MS, and theoretical modeling approaches.

Biological characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1/2 inhibitor.

Purpose: The Ras-Raf-mitogen-activated protein kinase kinase (MEK) pathway is overactive in many human cancers and is thus a target for novel therapeutics. We have developed a highly potent and selective inhibitor of MEK1/2. The purpose of these studies has been to show the biological efficacy of ARRY-142886 (AZD6244) in enzymatic, cellular, and animal models.

EPR study of substrate binding to the Mn(II) active site of the bacterial antibiotic resistance enzyme FosA: a better way to examine Mn(II).

FosA is a manganese metalloglutathione transferase that confers resistance to the broad-spectrum antibiotic fosfomycin, (1R,2S)-epoxypropylphosphonic acid. The reaction catalyzed by FosA involves the attack by glutathione on fosfomycin to yield the product 1-(S-glutathionyl)-2-hydroxypropylphosphonic acid. The enzyme is a dimer of 16 kDa subunits, each of which harbors one mononuclear Mn(II) site.