ORCID Profile
0000-0001-8422-675X
Current Organisation
Monash University
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Characterisation of Biological Macromolecules | Medicinal and Biomolecular Chemistry | Cheminformatics and Quantitative Structure-Activity Relationships | Biologically Active Molecules
Expanding Knowledge in the Chemical Sciences | Expanding Knowledge in the Biological Sciences |
Publisher: Springer Science and Business Media LLC
Date: 17-10-2016
Abstract: Macrocycles are of increasing interest as chemical probes and drugs for intractable targets like protein-protein interactions, but the determinants of their cell permeability and oral absorption are poorly understood. To enable rational design of cell-permeable macrocycles, we generated an extensive data set under consistent experimental conditions for more than 200 non-peptidic, de novo-designed macrocycles from the Broad Institute's ersity-oriented screening collection. This revealed how specific functional groups, substituents and molecular properties impact cell permeability. Analysis of energy-minimized structures for stereo- and regioisomeric sets provided fundamental insight into how dynamic, intramolecular interactions in the 3D conformations of macrocycles may be linked to physicochemical properties and permeability. Combined use of quantitative structure-permeability modeling and the procedure for conformational analysis now, for the first time, provides chemists with a rational approach to design cell-permeable non-peptidic macrocycles with potential for oral absorption.
Publisher: American Chemical Society (ACS)
Date: 25-10-2018
DOI: 10.1021/ACS.JMEDCHEM.8B01555
Abstract: Targets that have large and groove-shaped binding sites, such as cyclophilin, are difficult to drug with small molecules. Macrocycles of natural product origin can be ideal starting points for such targets as illustrated by the transformation of sanglifehrin A into an orally bioavailable potential candidate drug. Optimization benefits from development of convergent, modular synthetic routes in combination with structure and property based methods for lead optimization.
Publisher: American Chemical Society (ACS)
Date: 02-04-2018
DOI: 10.1021/ACS.JMEDCHEM.8B00347
Abstract: Conformational flexibility has been proposed to significantly affect drug properties outside rule-of-5 (Ro5) chemical space. Here, we investigated the influence of dynamically exposed polarity on cell permeability and aqueous solubility for a structurally erse set of drugs and clinical candidates far beyond the Ro5, all of which populated multiple distinct conformations as revealed by X-ray crystallography. Efflux-inhibited (passive) Caco-2 cell permeability correlated strongly with the compounds' minimum solvent-accessible 3D polar surface areas (PSA), whereas aqueous solubility depended less on the specific 3D conformation. Inspection of the crystal structures highlighted flexibly linked aromatic side chains and dynamically forming intramolecular hydrogen bonds as particularly effective in providing "chameleonic" properties that allow compounds to display both high cell permeability and aqueous solubility. These structural features, in combination with permeability predictions based on the correlation to solvent-accessible 3D PSA, should inspire drug design in the challenging chemical space far beyond the Ro5.
Publisher: Elsevier BV
Date: 06-2018
DOI: 10.1016/J.CBPA.2018.05.010
Abstract: Recent years have seen a dramatic increase in the number of drugs approved in chemical space outside of Lipinski's rule of 5, that is in what has been termed beyond rule of 5 (bRo5) space. The development of three major classes of oral drugs that treat HIV and HCV infections and the growing evidence that novel, difficult targets can be accessed has prompted research into understanding design of drugs displaying cell permeability, solubility and ultimately oral bioavailability in bRo5 space. Studies have found a consistent outer property limit for a reasonable chance of de novo designing oral bioavailability. In addition, several property-based guidelines, along with incorporation of chameleonic features, have emerged as strategies to aid design in bRo5 space. A more detailed understanding of the complex and environment dependent conformational landscape will likely be the focus of the next generation of guidelines allowing property predictions of ever more complex compounds. By pushing the boundaries of current orally designable chemical space we hope that discoveries will be made for fundamental science and also for discovery of novel therapeutics.
Publisher: Wiley
Date: 14-07-2017
Publisher: Wiley
Date: 27-01-2022
Abstract: DsbA enzymes catalyze oxidative folding of proteins that are secreted into the periplasm of Gram‐negative bacteria, and they are indispensable for the virulence of human pathogens such as Vibrio cholerae and Escherichia coli . Therefore, targeting DsbA represents an attractive approach to control bacterial virulence. X‐ray crystal structures reveal that DsbA enzymes share a similar fold, however, the hydrophobic groove adjacent to the active site, which is implicated in substrate binding, is shorter and flatter in the structure of V. cholerae DsbA (VcDsbA) compared to E. coli DsbA (EcDsbA). The flat and largely featureless nature of this hydrophobic groove is challenging for the development of small molecule inhibitors. Using fragment‐based screening approaches, we have identified a novel small molecule, based on the benzimidazole scaffold, that binds to the hydrophobic groove of oxidized VcDsbA with a K D of 446±10 μM. The same benzimidazole compound has ∼8‐fold selectivity for VcDsbA over EcDsbA and binds to oxidized EcDsbA, with K D .5 mM. We generated a model of the benzimidazole complex with VcDsbA using NMR data but were unable to determine the structure of the benzimidazole bound EcDsbA using either NMR or X‐ray crystallography. Therefore, a structural basis for the observed selectivity is unclear. To better understand ligand binding to these two enzymes we crystallized each of them in complex with a known ligand, the bile salt sodium taurocholate. The crystal structures show that taurocholate adopts different binding poses in complex with VcDsbA and EcDsbA, and reveal the protein‐ligand interactions that stabilize the different modes of binding. This work highlights the capacity of fragment‐based drug discovery to identify inhibitors of challenging protein targets. In addition, it provides a starting point for development of more potent and specific VcDsbA inhibitors that act through a novel anti‐virulence mechanism.
Publisher: Elsevier
Date: 2018
DOI: 10.1016/BS.MIE.2018.09.018
Abstract: Herein we describe a method for the design, purchase, and assembly of a fragment-screening library from a list of commercially available compounds. The computational tools used in assessment of compound properties as well as the workflow for compound selection are provided for reference as implemented in commercially available software that is free and accessible to most academic users. The workflow can be modified as necessary to generate a fit-for-purpose fragment library with the desired compound property profiles. An analytical process for assessing the quality, identity, and suitability of a purchased fragment for inclusion in a screening collection is described. Results from our in-house library are presented as an ex le of compound progression through this quality control process.
Publisher: American Chemical Society (ACS)
Date: 25-03-2020
DOI: 10.26434/CHEMRXIV.12026952.V1
Abstract: The development of low-affinity fragment hits into higher affinity leads is a major hurdle in fragment-based drug design. Here we demonstrate an approach for the Rapid Elaboration of Fragments into Leads (REFiL) applying an integrated workflow that provides a systematic approach to generate higher-affinity binders without the need for structural information. The workflow involves the selection of commercial analogues of fragment hits to generate preliminary structure-activity relationships. This is followed by parallel microscale chemistry using chemoinformatically designed reagent libraries to rapidly explore chemical ersity. Upon completion of a fragment screen against Bromodomain-3 extra terminal (BRD3-ET) domain we applied the REFiL workflow, which allowed us to develop a series of tetrahydrocarbazole ligands that bind to the peptide binding site of BRD3-ET. With REFiL we were able to rapidly improve binding affinity -fold. The REFiL workflow can be applied readily to a broad range of protein targets without the need of a structure, allowing the efficient evolution of low-affinity fragments into higher affinity leads and chemical probes.
Publisher: Elsevier BV
Date: 03-2019
Publisher: American Chemical Society (ACS)
Date: 12-01-2011
DOI: 10.1021/OL102852Z
Abstract: Bis(1,2,3-triazole)s have attracted recent interest as coordinating ligands for transition metals. Here we report a rapid, modular method for the synthesis of 1,1'-disubstituted-4,4'-linked unsymmetrical bis(1,2,3-triazole)s. The method employs sequential copper catalyzed azide-alkyne cycloaddition and deprotection steps on a monosilylbutadiyne. TMS (trimethylsilyl) and TIPS (triisopropylsilyl) were both investigated with TIPS being the preferred protecting group due to increased stability. The reactions were amenable to one-pot synthesis, and an optimized one-pot, three-step procedure was developed.
Publisher: Elsevier BV
Date: 09-2014
DOI: 10.1016/J.CHEMBIOL.2014.08.013
Abstract: The rule of 5 (Ro5) is a set of in silico guidelines applied to drug discovery to prioritize compounds with an increased likelihood of high oral absorption. It has been influential in reducing attrition due to poor pharmacokinetics over the last 15 years. However, strict reliance on the Ro5 may have resulted in lost opportunities, particularly for difficult targets. To identify opportunities for oral drug discovery beyond the Ro5 (bRo5), we have comprehensively analyzed drugs and clinical candidates with molecular weight (MW) > 500 Da. We conclude that oral drugs are found far bRo5 and properties such as intramolecular hydrogen bonding, macrocyclization, dosage, and formulations can be used to improve bRo5 bioavailability. Natural products and structure-based design, often from peptidic leads, are key sources for oral bRo5 drugs. These insights should help guide the design of oral drugs in bRo5 space, which is of particular interest for difficult targets.
Publisher: Worldwide Protein Data Bank
Date: 21-01-2015
DOI: 10.2210/PDB4WF5/PDB
Publisher: Informa UK Limited
Date: 08-12-2016
Publisher: Elsevier BV
Date: 11-2016
DOI: 10.1016/J.PHARMTHERA.2016.07.003
Abstract: Fragment-based drug design (FBDD) has emerged as a mainstream approach for the rapid and efficient identification of building blocks that can be used to develop high-affinity ligands against protein targets. One of the strengths of FBDD is the relative ease and low cost of the primary screen to identify fragments that bind. However, the fragments that emerge from primary screens often have low affinities, with K
Publisher: Walter de Gruyter GmbH
Date: 03-03-2020
Abstract: Investigation of hemostasis is problematic when patients are on anticoagulant therapy. Rivaroxaban especially causes substantial interference, extending many clot-based tests, thereby leading to false positive or negative events. In particular, rivaroxaban affects some assays for activated protein C resistance (APCR). We assessed, in an international setting, cross laboratory (n = 31) testing using four s les to evaluate rivaroxaban induced interference in APCR testing, and whether this interference could be neutralised. The s les comprised: (A) pool of normal plasma (APCR-negative control) (B) this normal pool spiked with rivaroxaban (200 ng/mL) to create rivaroxaban-induced interference (potential ‘false’ positive APCR event s le) (C) the rivaroxaban s le subsequently treated with a commercial direct oral anticoagulant ‘DOAC-neutraliser’ (DOAC Stop), or (D) treated with andexanet alfa (200 μg/mL). Testing was performed blind to s le type. The rivaroxaban-spiked s le generated false positive APCR results for some, but unexpectedly not most APCR-tests. The s le treated with DOAC Stop evidenced a correction in the rivaroxaban-affected APCR assays, and did not otherwise adversely affect the rivaroxaban ‘unaffected’ APCR assays. The andexanet alfa-treated s le did not evidence correction of the false positive APCR, and instead unexpectedly exacerbated false positive APCR status with many tests. DOAC Stop was able to neutralise any APCR interference induced by rivaroxaban. In contrast, andexanet alfa did not negate such interference, and instead unexpectedly created more false-positive APCR events.
Publisher: Springer Science and Business Media LLC
Date: 18-07-2017
Publisher: Elsevier BV
Date: 06-2016
DOI: 10.1016/J.ADDR.2016.03.013
Abstract: Drug discovery for difficult targets that have large and flat binding sites is often better suited to compounds beyond the "rule of 5" (bRo5). However, such compounds carry higher pharmacokinetic risks, such as low solubility and permeability, and increased efflux and metabolism. Interestingly, recent drug approvals and studies suggest that cell permeable and orally bioavailable drugs can be discovered far into bRo5 space. Tactics such as reduction or shielding of polarity by N-methylation, bulky side chains and intramolecular hydrogen bonds may be used to increase cell permeability in this space, but often results in decreased solubility. Conformationally flexible compounds can, however, combine high permeability and solubility, properties that are keys for cell permeability and intestinal absorption. Recent developments in computational conformational analysis will aid design of such compounds and hence prediction of cell permeability. Transporter mediated efflux occurs for most investigated drugs in bRo5 space, however it is commonly overcome by high local intestinal concentrations on oral administration. In contrast, there is little data to support significant impact of transporter-mediated intestinal absorption in bRo5 space. Current knowledge of compound properties that govern transporter effects of bRo5 drugs is limited and requires further fundamental and comprehensive studies.
Publisher: Springer Science and Business Media LLC
Date: 06-08-2020
Publisher: American Chemical Society (ACS)
Date: 17-02-2022
DOI: 10.26434/CHEMRXIV-2022-262LH
Abstract: Disulfide bond protein A (DsbA) is an oxidoreductase enzyme that catalyzes the formation of disulfide bonds in Gram-negative bacteria. In Escherichia coli, DsbA (EcDsbA) is essential for bacterial virulence, thus inhibitors have the potential to act as antivirulence agents. A fragment-based screen was conducted against EcDsbA and herein we describe the development of a series of compounds based on a phenylthiophene hit identified from the screen. A novel thiol reactive and “clickable” ethynylfluoromethylketone was designed for reaction with azide-functionalized fragments to enable rapid and versatile attachment to a range of fragments. The resulting fluoromethylketone conjugates showed selectivity for reaction with the active site thiol of EcDsbA, however unexpectedly, turnover of the covalent adduct was observed. A mechanism for this turnover was investigated and proposed which may have wider ramifications for covalent reactions with dithiol-disulfide oxidoreducatases.
Publisher: Worldwide Protein Data Bank
Date: 21-01-2015
DOI: 10.2210/PDB4WF4/PDB
Publisher: Worldwide Protein Data Bank
Date: 11-05-2016
DOI: 10.2210/PDB4ZIJ/PDB
Publisher: Royal Society of Chemistry (RSC)
Date: 2023
DOI: 10.1039/D2MD00253A
Abstract: Small molecule interaction hotpots were identified by screening small, low complexity fragments using X-ray crystallography. These hot spots include cryptic pockets and provide pharmacophore mapping that may be used in structure-based drug design.
Publisher: Wiley
Date: 11-10-2019
Abstract: Drugs in the chemical space beyond the rule of 5 (bRo5) can modulate targets with difficult binding sites while retaining cell permeability and oral absorption. Reviewing the syntheses of bRo5 drugs approved since 1990 highlights synthetic chemistry's contribution to drug discovery in this space. Initially, bRo5 drugs were mainly natural products and semi‐synthetic derivatives. Later, peptidomimetics and de novo designed compounds, that include up to seven chiral centres and macrocyclic rings became dominant. These drugs are prepared by total synthesis, sometimes by routes of more than 25 steps with stereocentres originating from the chiral pool, or being installed by chiral induction or enzymatic resolution. Interestingly, ring‐closing metathesis proved to be the method of choice for macrocyclisation in hepatitis C virus protease inhibitors. We conclude that structural simplification, planning of synthetic routes regarding incorporation of stereocentres and macrocyclisation, as well as incorporation of structural knowledge and consideration of chameleonic properties in design, should facilitate drug discovery in bRo5 space.
Publisher: Springer International Publishing
Date: 2018
Publisher: Worldwide Protein Data Bank
Date: 21-01-2015
DOI: 10.2210/PDB4WEY/PDB
Publisher: Wiley
Date: 30-12-2014
Abstract: The thiol-disulfide oxidoreductase enzyme DsbA catalyzes the formation of disulfide bonds in the periplasm of Gram-negative bacteria. DsbA substrates include proteins involved in bacterial virulence. In the absence of DsbA, many of these proteins do not fold correctly, which renders the bacteria avirulent. Thus DsbA is a critical mediator of virulence and inhibitors may act as antivirulence agents. Biophysical screening has been employed to identify fragments that bind to DsbA from Escherichia coli. Elaboration of one of these fragments produced compounds that inhibit DsbA activity in vitro. In cell-based assays, the compounds inhibit bacterial motility, but have no effect on growth in liquid culture, which is consistent with selective inhibition of DsbA. Crystal structures of inhibitors bound to DsbA indicate that they bind adjacent to the active site. Together, the data suggest that DsbA may be amenable to the development of novel antibacterial compounds that act by inhibiting bacterial virulence.
Publisher: American Chemical Society (ACS)
Date: 30-10-2015
DOI: 10.1021/ACS.JMEDCHEM.5B01286
Abstract: To improve discovery of drugs for difficult targets, the opportunities of chemical space beyond the rule of 5 (bRo5) were examined by retrospective analysis of a comprehensive set of structures for complexes between drugs and clinical candidates and their targets. The analysis illustrates the potential of compounds far beyond rule of 5 space to modulate novel and difficult target classes that have large, flat, and groove-shaped binding sites. However, ligand efficiencies are significantly reduced for flat- and groove-shape binding sites, suggesting that adjustments of how to use such metrics are required. Ligands bRo5 appear to benefit from an appropriate balance between rigidity and flexibility to bind with sufficient affinity to their targets, with macrocycles and nonmacrocycles being found to have similar flexibility. However, macrocycles were more disk- and spherelike, which may contribute to their superior binding to flat sites, while rigidification of nonmacrocycles lead to rodlike ligands that bind well to groove-shaped binding sites. These insights should contribute to altering perceptions of what targets are considered "druggable" and provide support for drug design in beyond rule of 5 space.
Publisher: American Chemical Society (ACS)
Date: 12-06-2020
Publisher: Elsevier BV
Date: 12-2009
DOI: 10.1016/J.JMB.2009.09.065
Abstract: Neisseria meningitidis encodes three DsbA oxidoreductases (NmDsbA1-NmDsbA3) that are vital for the oxidative folding of many membrane and secreted proteins, and these three enzymes are considered to exhibit different substrate specificities. This has led to the suggestion that each N. meningitidis DsbA (NmDsbA) may play a specialized role in different stages of pathogenesis however, the molecular and structural bases of the different roles of NmDsbAs are unclear. With the aim of determining the molecular basis for substrate specificity and how this correlates to pathogenesis, we undertook a biochemical and structural characterization of the three NmDsbAs. We report the 2.0-A-resolution crystal structure of the oxidized form of NmDsbA1, which adopted a canonical DsbA fold similar to that observed in the structures of NmDsbA3 and Escherichia coli DsbA (EcDsbA). Structural comparisons revealed variations around the active site and candidate peptide-binding region. Additionally, we demonstrate that all three NmDsbAs are strong oxidases with similar redox potentials however, they differ from EcDsbA in their ability to be reoxidized by E. coli DsbB. Collectively, our studies suggest that the small structural differences between the NmDsbA enzymes and EcDsbA are functionally significant and are the likely determinants of substrate specificity.
Publisher: CSIRO Publishing
Date: 2013
DOI: 10.1071/CH13280
Abstract: The design of a suitable library is an essential prerequisite to establish a fragment-based screening capability. Several pharmaceutical companies have described their approaches to establishing fragment libraries however there are few detailed reports of both design and analysis of performance for a fragment library maintained in an academic setting. Here we report our efforts towards the design of a fragment library for nuclear magnetic resonance spectroscopy-based screening, demonstrate the performance of the library through analysis of 14 screens, and present a comparison to previously reported fragment libraries.
Start Date: 2020
End Date: 2022
Funder: Australian Research Council
View Funded ActivityStart Date: 2020
End Date: 12-2022
Amount: $670,000.00
Funder: Australian Research Council
View Funded Activity