Modelling Atypical Small‐Molecule Mimics of an Important Stem Cell Cytokine, Thrombopoietin

Tarasova, Anna; Winkler, David A.

doi:10.1002/cmdc.200900340

Cited by 8 publications

(7 citation statements)

References 50 publications

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“…One of our goals is to understand how small‐molecule compounds like the drug eltromopobag, thought to bind the TM domain of TpoR, can lead to receptor activation. A new class of these molecules has been identified (38), and we used one of these, a piperidine‐4‐carboxylic acid (compound PF in Fig. 6 A ) to probe TpoR TM domain interactions and the mechanisms involved in receptor activation.…”

Section: Resultsmentioning

confidence: 99%

“…5 C ). So, it is unlikely that a single planar molecule, binding to His499 with its Lewis basic group at one end, is binding to all the positions affected by alanine substitution (31, 38). Thus, we propose, as an alternative complementary explanation, that alanine substitutions at these 5 sensitive TM positions destabilize the active state of the receptor TM dimer interface.…”

Section: Discussionmentioning

confidence: 99%

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Thrombopoietin receptor activation: transmembrane helix dimerization, rotation, and allosteric modulation

Matthews

Thévenin²,

Rogers³

et al. 2011

FASEB j.

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We report how rotational variations in transmembrane (TM) helix interactions participate in the activity states of the thrombopoietin receptor (TpoR), a type 1 cytokine receptor that controls the production of blood platelets. We also explore the mechanism of small-molecule agonists that do not mimic the natural ligand. We show, by a combination of cysteine cross-linking, alanine-scanning mutagenesis, and computational simulations, that the TpoR TM dimerizes strongly and can adopt 3 different stable, rotationally related conformations, which may correspond to specific states of the full-length receptor (active, inactive, and partially active). Thus, our data suggest that signaling and inactive states of the receptor are related by receptor subunit rotations, rather than a simple monomer-dimer transition. Moreover, results from experiments with and without agonists in vitro and in cells allow us to propose a novel allosteric mechanism of action for a class of small molecules, in which they activate TpoR by binding to the TM region and by exploiting the rotational states of the dimeric receptor. Overall, our results support the emerging view of the participation of mutual rotations of the TM domains in cytokine receptor activation.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Thrombopoietin receptor activation: transmembrane helix dimerization, rotation, and allosteric modulation

Matthews

Thévenin²,

Rogers³

et al. 2011

FASEB j.

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“…Eltrombopag is of particular interest as an M pro inhibitor lead because it is novel and is also a member of a large class of small molecular TPO receptor agonists that may also exhibit activity against the viral protease, and potentially the spike protein and human ACE2. ( Tarasova and Winkler, 2009 ). However, given the clotting disorders that SAR-CoV-2 generates, the TPOR agonist activities would need to be minimized to prevent platelet enhancement, while retaining or enhancing the antiviral activities.…”

Section: Resultsmentioning

confidence: 99%

Computational Repurposing of Drugs and Natural Products Against SARS-CoV-2 Main Protease (Mpro) as Potential COVID-19 Therapies

Piplani

Singh

Petrovsky

et al. 2022

Front. Mol. Biosci.

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We urgently need to identify drugs to treat patients suffering from COVID-19 infection. Drugs rarely act at single molecular targets. Off-target effects are responsible for undesirable side effects and beneficial synergy between targets for specific illnesses. They have provided blockbuster drugs, e.g., Viagra for erectile dysfunction and Minoxidil for male pattern baldness. Existing drugs, those in clinical trials, and approved natural products constitute a rich resource of therapeutic agents that can be quickly repurposed, as they have already been assessed for safety in man. A key question is how to screen such compounds rapidly and efficiently for activity against new pandemic pathogens such as SARS-CoV-2. Here, we show how a fast and robust computational process can be used to screen large libraries of drugs and natural compounds to identify those that may inhibit the main protease of SARS-CoV-2. We show that the shortlist of 84 candidates with the strongest predicted binding affinities is highly enriched (≥25%) in compounds experimentally validated in vivo or in vitro to have activity in SARS-CoV-2. The top candidates also include drugs and natural products not previously identified as having COVID-19 activity, thereby providing leads for experimental validation. This predictive in silico screening pipeline will be valuable for repurposing existing drugs and discovering new drug candidates against other medically important pathogens relevant to future pandemics.

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“…These methods have been used to design and optimise green pesticides [16][17][18][19][20] in collaboration with Du Pont and Schering Plough, have discovered new peptides and small molecules to control stem cells and cancers, [21][22][23][24][25][26][27] are accelerating the development of biomaterials for implantation and stem cell culture, [28][29][30][31][32][33] have provided new scientific insight into the potential adverse properties of nanomaterials, [34][35][36][37][38] have yielded clinical candidates for Australian SMEs and international companies, and were instrumental in the discovery of antibiotics [39,40] with a novel mode of action for the biotechnology spin off company, Betabiotics. Some of this research is discussed in more detail in the following sections.…”

Section: The Threat and Promise Of The Vastness Of Chemical Spacementioning

confidence: 99%

“…We identified a key binding motif, RQW, in these peptide libraries and used this to develop potent small molecule and peptide agonists and antagonists of the TPO receptor. [22,23] The agonists were capable of potently stimulating platelet counts in animals, and also increased megakaryocyte ploidy. Peptide TPO mimetics could replace native TPO in the expansion of CD34 þ CD38 À primary cells up to 8 days.…”

Section: Self-assembling Amphiphilic Drug Delivery Systemsmentioning

confidence: 99%

Adrien Albert Award: How to Mine Chemistry Space for New Drugs and Biomedical Therapies

Winkler

2015

Aust. J. Chem.

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It is clear that the sizes of chemical, 'drug-like', and materials spaces are enormous. If scientists working in established therapeutic, and newly established regenerative medicine fields are to discover better molecules or materials, they must find better ways of probing these enormous spaces. There are essentially five ways that this can be achieved: combinatorial and high throughput synthesis and screening approaches; fragment-based methods; de novo molecular design, design of experiments, diversity libraries; supramolecular approaches; evolutionary approaches. These methods either synthesise materials and screen them more quickly, or constrain chemical spaces using biology or other types of 'fitness functions'. High throughput experimental approaches cannot explore more than a minute part of chemical space. We are nevertheless entering into an era that is data dominated. High throughput experiments, robotics, automated crystallographic beam lines, combinatorial and flow synthesis, high content screening, and the 'omics' technologies are providing a flood of data, and efficient methods for extracting meaning from it are essential. This paper describes how new developments in mathematics have provided excellent, robust computational modelling tools for exploring large chemical spaces, for extracting meaning from large datasets, for designing new bioactive agents and materials, and for making truly predictive, quantitative models of the properties of molecules and materials for use in therapeutic and regenerative medicine. We describe these broadly applicable modelling tools and provide examples of their application to serum free stem cell culture, pathogen resistant polymers for implantable devices, new markers and biological mechanisms derived from mathematical analyses of gene array data, and pharmacokinetically important physicochemical properties of small molecules. We also discuss biologically conserved peptide motifs as a design framework for small molecule drugs and give examples of the application of this concept to drug design.

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Modelling Atypical Small‐Molecule Mimics of an Important Stem Cell Cytokine, Thrombopoietin

Cited by 8 publications

References 50 publications

Thrombopoietin receptor activation: transmembrane helix dimerization, rotation, and allosteric modulation

Thrombopoietin receptor activation: transmembrane helix dimerization, rotation, and allosteric modulation

Computational Repurposing of Drugs and Natural Products Against SARS-CoV-2 Main Protease (Mpro) as Potential COVID-19 Therapies

Adrien Albert Award: How to Mine Chemistry Space for New Drugs and Biomedical Therapies

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