ORCID Profile
0000-0002-4613-7999
Current Organisation
Monash University
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Publisher: American Chemical Society (ACS)
Date: 02-12-2016
Publisher: Royal Society of Chemistry (RSC)
Date: 2012
DOI: 10.1039/C2CP41625E
Abstract: We report on the use of protic ionic liquids, pILs, as solvents for the solubilisation and stabilization of viruses. We show that the shelf life of the pIL stabilized tobacco mosaic virus is significantly enhanced when compared to traditional phosphate buffer. This has new opportunities for the preparation, characterization and storage of viruses and virus based technologies.
Publisher: American Chemical Society (ACS)
Date: 17-07-2014
DOI: 10.1021/JM500191U
Abstract: A whole-organism screen of approximately 87000 compounds against Trypanosoma brucei brucei identified a number of promising compounds for medicinal chemistry optimization. One of these classes of compounds we termed the pyridyl benzamides. While the initial hit had an IC50 of 12 μM, it was small enough to be attractive for further optimization, and we utilized three parallel approaches to develop the structure-activity relationships. We determined that the physicochemical properties for this class are generally favorable with particular positions identified that appear to block metabolism when substituted and others that modulate solubility. Our most active compound is 79, which has an IC50 of 0.045 μM against the human pathogenic strain Trypanosoma brucei rhodesiense and is more than 4000 times less active against the mammalian L6 cell line.
Publisher: CSIRO Publishing
Date: 2012
DOI: 10.1071/CH12316
Abstract: We report on the impact of changes in the protic ionic liquid (pIL) cation on the fibrilisation kinetics and the conversion of the Aβ 16–22 from monomers to amyloid fibrils. When we compare the use of primary, secondary, and tertiary amines we find that the primary amine results in the greatest conversion into amyloid fibrils. We show that the pIL is directly interacting with the peptide and this likely drives the difference in conversion and kinetics observed.
Publisher: American Chemical Society (ACS)
Date: 09-09-2020
Publisher: Cold Spring Harbor Laboratory
Date: 14-08-2019
DOI: 10.1101/730622
Abstract: The human M 5 muscarinic acetylcholine receptor (mAChR) has recently emerged as an exciting therapeutic target for treating a range of disorders, including drug addiction. However, a lack of structural information for this receptor subtype has limited further drug development and validation. Here we report a high-resolution crystal structure of the human M 5 mAChR bound to the clinically used inverse agonist, tiotropium. This structure allowed for a comparison across all five mAChR family members that revealed important differences in both orthosteric and allosteric sites that could inform the rational design of selective ligands. These structural studies together with chimeric swaps between the extracellular regions of the M 2 and M 5 mAChR further revealed the structural insight into “kinetic-selectivity”, where ligands show differential residency times between related family members. Collectively, our study provides important insights into the nature of orthosteric and allosteric ligand interaction across the mAChR family that could be exploited for the design of selective ligands. The five subtypes of the muscarinic acetylcholine receptors (mAChRs) are expressed throughout the central and peripheral nervous system where they play a vital role in physiology and pathologies. Recently, the M 5 mAChR subtype has emerged as an exciting drug target for the treatment of drug addiction. We have determined the atomic structure of the M 5 mAChR bound to the clinically used inverse agonist tiotropium. The M 5 mAChR structure now allows for a full comparison of all five mAChR subtypes and reveals subtle differences in the extracellular loop (ECL) regions of the receptor that mediate orthosteric and allosteric ligand selectivity. Together these findings open the door for future structure-based design of selective drugs that target this therapeutically important class of receptors.
Publisher: Elsevier BV
Date: 06-2018
DOI: 10.1016/J.CHEMBIOL.2018.03.008
Abstract: The AMP-activated protein kinase (AMPK) αβγ heterotrimer regulates cellular energy homeostasis with tissue-specific isoform distribution. Small-molecule activation of skeletal muscle α2β2 AMPK complexes may prove a valuable treatment strategy for type 2 diabetes and insulin resistance. Herein, we report the small-molecule SC4 is a potent, direct AMPK activator that preferentially activates α2 complexes and stimulates skeletal muscle glucose uptake. In parallel with the term secretagog, we propose "importagog" to define a substance that induces or augments cellular uptake of another substance. Three-dimensional structures of the glucose importagog SC4 bound to activated α2β2γ1 and α2β1γ1 complexes reveal binding determinants, in particular a key interaction between the SC4 imidazopyridine 4'-nitrogen and β2-Asp111, which provide a design paradigm for β2-AMPK therapeutics. The α2β2γ1/SC4 structure reveals an interaction between a β2 N-terminal α helix and the α2 autoinhibitory domain. Our results provide a structure-function guide to accelerate development of potent, but importantly tissue-specific, β2-AMPK therapeutics.
No related grants have been discovered for Swapna Varghese.