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Drug Discovery

The UCL drug discovery laboratories run by Professor David Selwood and Professor Edith Chan conduct research in medicinal chemistry and computational drug design to combat major diseases such as multiple sclerosis, cancer, HIV, and associated viruses. We spearhead innovative research, seamlessly integrating computational molecular design, medicinal chemistry, and rigorous biological assay testing across our investigations.

Medicinal Chemistry

Principal Investigator: Prof. David Selwood

The David Selwood Lab conducts research on the edge of chemistry and biology using the latest techniques and developing new ones for the study of biological systems. We use computational molecular design for much of our research, working with Prof. Edith Chan. We also collaborate extensively with biologists in academia and industry.

Multiple Sclerosis

New prototype drug (VSN16R) for spasticity related conditions in MS

Key biological collaborator: Prof. David Baker

VSN16R is a new type of prototype MS drug that has the potential to alleviate spasticity in MS patients. It is an activator of big conductance potassium channels (BK channels). Originally, this compound was synthesised by Dr Cristina Visintin aided by Dr Masahiro Okuyama in the Selwood Lab. It was tested by Prof. David Baker and Gareth Pryce at the Institute of Neurology, UCL, prior to moving to Barts.

The work was initially funded by the Brain Research Trust and the Wellcome Trust. VSN16 and related compounds are currently being developed by UCL spinout company, Canbex Therapeutics, which is backed by Bloomsbury Bioseed Fund, Esperante Ventures and UCL Business plc. Other funders include the National Multiple Sclerosis Society (NMSS).

References

Baker D, Pryce G, Visintin C, Sisay S, Bondarenko AI, Vanessa Ho WS, Jackson SJ, Williams TE, Al-Izki S, Sevastou I, Okuyama M, Graier WF, Stevenson LA, Tanner C, Ross R, Pertwee RG, Henstridge CM, Irving AJ, Schulman J, Powell K, Baker MD, Giovannoni G, Selwood DL (2017). Big conductance calcium-activated potassium channel openers control spasticity without sedation. Br J Pharmacol. 2017 Aug;174(16):2662-2681.

Neuroprotection: using sodium channel blockers to maintain nerve function in MS

Key biological collaborator: Prof. John Garthwaite (UCL); Prof. David Baker

Voltage-gated sodium channels are found in the cell membranes of electrically excitable cells and are fundamental to the generation of electrical impulses (nerve impulses). There are nine different sodium channels in humans (Nav1.1 to Nav1.9). In multiple sclerosis the protective layer (the myelin) becomes degraded by an auto-immune response and the nerves no longer conduct electrical impulses efficiently. After some time, demyelinated nerves degenerate and die. Overactivity of sodium channels is implicated in the process of cell death, and we are investigating whether sodium channel blockers that show selectivity for individual channels may be useful in MS. A early prototype compound is CFM1178 and later molecules include CFM6104.

References

Browne L, Lidster K, Al-Izki S, Clutterbuck L, Posada C, Chan AW, Riddall D, Garthwaite J, Baker D, Selwood DL (2014). Imidazol-1-ylethylindazole voltage-gated sodium channel ligands are neuroprotective during optic neuritis in a mouse model of multiple sclerosis. J Med Chem. 2014 Apr 10;57(7):2942-52. Erratum in: J Med Chem. 2015 Apr 23;58(8):3637.

Al-Izki S, Pryce G, Hankey DJ, Lidster K, von Kutzleben SM, Browne L, Clutterbuck L, Posada C, Chan AWE, Amor S, Perkins V, Gerritsen WH, Ummenthum K, Peferoen-Baert R, van der Valk P, Montoya A, Joel SP, Garthwaite J, Giovannoni G, Selwood DL, Baker D (2014). Lesional-targeting of neuroprotection to the inflammatory penumbra in experimental multiple sclerosis. Brain. 2014, 137(Pt 1): 92-108.

Cyclosporin: Mitochondrial targeting of therapeutic agents

Key biological collaborator: Prof. Martin Crompton (UCL), Dr Alun Coker (UCL).

Cyclosporin is a large cyclic peptide that can bind to several cellular proteins. In mitochondria cyclosporin binds to the cyclophilin D protein. Cyclophilin D has recently attracted much attention as a potential target for treating ischaemia reperfusion injury and for neuroprotection. We have successfully targeted cyclosporin to mitochondria by including a lipophilic cation targeting group. This makes use of the large (negative inside) potential difference between the outside of mitochondria and the inside. Extension of this work to include quinolinium cations has broadened the scope of the method.

References

Warne J, Pryce G, Hill JM, Shi X, Lennerås F, Puentes F, Kip M, Hilditch L, Walker P, Simone MI, Chan AW, Towers GJ, Coker AR, Duchen MR, Szabadkai G, Baker D, Selwood DL (2016). Selective Inhibition of the Mitochondrial Permeability Transition Pore Protects against Neurodegeneration in Experimental Multiple Sclerosis. J Biol Chem. 2016 Feb 26;291(9):4356-73.

Crystalline form of the VSN16R compound

CFM1178 chemical structure

Targeting cyclosporin to mitochondria

New cancer agents

Small Molecule Carriers of Biomolecules (SMoCs)

We have designed and synthesized small-molecule mimics of an alpha-helical peptide protein transduction domain. These small-molecule carriers, which we termed SMoCs, are easily coupled to biomolecules, and efficiently deliver siRNA, dye molecules and recombinant proteins into a variety of cell types. We designed the SMoCs using molecular modelling techniques. As an example of a protein cargo, we applied this new technology to the internalization of the DNA replication licensing repressor geminin, in vitro, providing evidence that extracellularly delivered SMoC-geminin can have an antiproliferative effect on human cancer cells. Current work on this project is aimed at delivering siRNA.

References

Okuyama M, Laman H, Kingsbury SR, Visintin C, Leo E, Eward KL, Stoeber K, Boshoff C, Williams GH, Selwood DL (2007). Small-molecule mimics of an alpha-helix for efficient transport of proteins into cells. Nat Methods. 2007 Feb;4(2):153-9.

Neuropilin

Key biological collaborators: Prof. Stella Tsirka (Stony Brook), Prof. Snezana Djordjevic (ISMB, UCL), Prof. Ian Zachary (UCL) and Dr Paul Frankel (UCL).

Neuropilin is a receptor for vascular endothelial growth factor (VEGF) an important growth factor mediating the growth of new blood vessels (angiogenesis). Neuropilin has emerged as a novel target for cancer immunotherapy. Over several years we have developed novel peptide and small molecule inhibitors of this interaction.

References

Miyauchi JT, Chen D, Choi M, Nissen JC, Shroyer KR, Djordevic S, Zachary IC, Selwood D, Tsirka SE (2016). Ablation of Neuropilin 1 from glioma-associated microglia and macrophages slows tumor progression. Oncotarget. 2016 7(9):9801-14.

Cardiovascular

NPRC

Key biological collaborator: Prof. Adrian Hobbs (QMUL), Prof. Snezana Djordjevic (UCL).

Natriuretic peptides are large cyclic peptides that bind three related receptors NPR1-3. The third receptor NPR1 or NPRC is present in high concentration in cardiovascular and peripheral tissues, it is a potent relaxant of arterial and venous smooth muscle. Small molecule NPR3 agonists are potential treatments for heart failure and ischaemic reperfusion injury.

References

Moyes AJ, Khambata RS, Villar I, Bubb KJ, Baliga RS, Lumsden NG, Xiao F, Gane PJ, Rebstock AS, Worthington RJ, Simone MI, Mota F, Rivilla F, Vallejo S, Peiró C, Sánchez Ferrer CF, Djordjevic S, Caulfield MJ, MacAllister RJ, Selwood DL, Ahluwalia A, Hobbs AJ (2014). Endothelial C-type natriuretic peptide maintains vascular homeostasis. J Clin Invest. 2014 Sep;124(9): 4039-51.

HIV and other viruses

Cyclosporin as a viral target

Key biological collaborator: Prof. Greg Towers (UCL).

Viruses can suppress the immune system to enable cellular infection. Our work centres on the manipulation of cyclophilin proteins to affect innate immune sensing and control viral infection.

References

Rasaiyaah J, Tan CP, Fletcher AJ, Price AJ, Blondeau C, Hilditch L, Jacques DA, Selwood DL, James LC, Noursadeghi M, Towers GJ (2013). HIV-1 evades innate immune recognition through specific cofactor recruitment. Nature. 2013;503(7476):402-405.

Small-molecule carriers of biomolecules

NPRC: relaxant of arterial & venous smooth muscle

A scientist working on a computer with drug samples nearby

Computational Drug Design

PrincipaI Investigator: Prof. Edith Chan.

Professor Chan's research interests cover the spectrum of Molecular Modelling, Computational Chemistry, Cheminformatics, Bioinformatics, Database management, and AI Machine Learning.

Molecular Modelling

The vFLIP-IKKgamma Interaction as a Cancer Target

Key biological collaborator: Dr Tracey Barrett (Birkbeck).

Human herpes virus 8 is the causal agent of Kaposi's sarcoma, a disease common among immunocompromised patients particularly AIDS patients. One of the viral proteins that drives this cancer is called vFLIP. vFLIP interacts with a cellular protein, IKKγ, to initiate a chain of cellular events maintaining the cancer. A related cellular protein cFLIP is a promising cancer target for a wider range of cancers. We are developing inihibitors of the vFLIP and cFLIP - IKKgamma interactions.

This work is funded by Cancer Research UK.

References

Briggs LC, Chan AWE, Davis CA, Whitelock N, Hotiana HA, Baratchian M, Bagnéris C, Selwood DL, Collins MK, Barrett TE (2017). IKKγ-Mimetic Peptides Block the Resistance to Apoptosis Associated with Kaposi's Sarcoma-Associated Herpesvirus Infection. J Virol. 2017 91(23). pii: e01170-17.

Benzobisthiazoles represent a novel scaffold for kinase inhibitors of CLK family members

Key collaborators: Dr Janos Kriston-Vizi and Prof. Robin Ketteler (Lab for Molecular Cell Biology, MRC-UCL).

Protein kinases are essential regulators of most cellular processes and are involved in the etiology and progression of multiple diseases. The cdc2-like kinases (CLKs) have been linked to various neurodegenerative disorders, metabolic regulation, and virus infection, and the kinases have been recognized as potential drug targets. We propose models for binding of these compounds to CLK family proteins and key residues in CLK2 that are important for the compound interactions and the kinase activity.

We identified structural elements within the benzobisthiazole that determine CLK2 and CLK3 inhibition, thus providing a rationale for selectivity assays.

References

Prak K, Kriston-Vizi J, Chan AW, Luft C, Costa JR, Pengo N, Ketteler R. Benzobisthiazoles Represent a Novel Scaffold for Kinase Inhibitors of CLK Family Members. Biochemistry. 2016 Jan 26;55(3):608-17.

Student projects
  • Emily Knight: Targeting the ks-vFLIP Protein.
  • Sami Jaffar: Drug repositioning using Field technology.
  • Georgia Denning: Natural hormones and neurotransmitters as drug leads - How do they compare to other lead identification strategies?
  • Matteo Aldeghi: In-silico analysis of 3D molecular fragments in bioactive compounds. Two and Three-dimensional Rings in Drugs.
  • Shipra Malhotra: Analysis of protein-ligand interactions: a knowledge-based and quantitative approach.
  • Christina Founti: Analysis of 2D and 3D ring fragments in ligands of the protein data bank.
  • Jiayan Guan: Pharmacophore modelling and Quantitative Structure-Activity Relationship Study of HIF-1 alpha inhibitors.
  • Shuyi Zhang: Probing the fragment specificity and selectivity of kinases: a pilot study using fragment docking.
  • Arianna Oddo: Chemical fragments that have hydrogen bonds with a series of Amino Acids.
  • Xabier Cendoya: Garmendia LigandSchema: a tool for interactive graphing of PDB ligands and protein families.
  • Chin-Ping Kung: Small molecular design for inhibition of GEF-H1/RhoA.
  • Yanling Zhang: Hit generation of Brachyury using by structure-based virtual screening.
  • Edmondos Poyiadjis: In silico Drug Repositioning: Targeting an essential Malaria biosynthetic pathway.
  • Yanfei Li: Fragment-based drug design for Schistosomiasis.
  • Julie Erics: Virtual screening promiscuous drugs against plasmodium falciparum.
  • Sarah Martin: Docking of macrocycles using GOLD.
  • Jiaqi Hu: Drug design targeting the SH2 domain of PLC-gamma2.
  • Robert Nkwo: Relationship of 3D molecular similarity and protein families in drug discovery
  • Tanachote Ruengsatra: Drug design for Noroviral proteases.
  • Xiaotong Zhang: Maximum common substructure analysis of ligands in protein families.
  • Reuben Dawkins: Target Discovery, Drugability and Attractiveness in Type 3 Diabetes.
  • Run Chen Xu: Drug Binding selectivity of cP450 using machine learning modelling.
  • Dewei Ni: Prediction of compound selectivity using machine learning modelling in PPAR family.​​​​​​

X-ray structure of the vFLIP-IKKgamma interaction

Novel scaffold for CLK inhibitors

Cheminformatics and Databases

LigFrag – A database of protein side chain / ligand-fragment interactions

The following tables show the chemical fragments that interact via hydrogen bonds to the side chains of Asp, Glu, Arg, and His in protein-binding sites.

  1. Table S1: Aspartate
  2. Table S2: Glutamate
  3. Table S3: Arginine
  4. Table S4: Histidine

Reference

Chan AW, Laskowski RA, Selwood DL (2010). Chemical fragments that hydrogen bond to Asp, Glu, Arg, and His side chains in protein binding sites. J Med Chem. 2010 Apr 22;53(8):3086-94.

Ring Analysis in Drugs - comparisons of 2D and 3D fragments in drugs

Using small, flat aromatic rings as components of fragments or molecules is a common practice in fragment-based drug discovery and lead optimization. With an increasing focus on the exploration of novel biological and chemical space, and their improved synthetic accessibility, 3D fragments are attracting increasing interest. 

This study presents a detailed analysis of 3D and 2D ring fragments in marketed drugs. Several measures of properties were used, such as the type of ring assemblies and molecular shapes. The study also considered the relationship between protein classes targeted by each ring fragment, providing target-specific information. The analysis shows the high structural and shape diversity of 3D ring systems and their importance in bioactive compounds. Major differences in 2D and 3D fragments are apparent in ligands that bind to the major drug targets such as GPCRs, ion channels, and enzymes.

Reference

Aldeghi M, Malhotra S, Selwood DL, Chan AW (2014). Two- and three-dimensional rings in drugs. Chem Biol Drug Des. 2014 Apr;83(4):450-61.

LigNFam: Drug repositioning: in silico platform to study Drug-Protein relationships

LigNFam is an in-silico platform for investigation of the relationship of small molecules and protein family using the PDB data. Edith and PhD student, Oliver Scott are currently developing it.

Posters

  1. Classification and Analysis of Privileged Scaffolds in Protein Families (PDF)
  2. Evaluation of Compound Selectivity in PPAR Family using Machine Learning Modelling (PDF)
ScaffoldGraph (SG) - an open-source Python library

ScaffoldGraph is an open-source Python library and command-line tool to generate and analyse molecular scaffold networks and trees, with the capability of processing large sets of input molecules. With the increase in high-throughput screening data, scaffold graphs have proven useful for the navigation and analysis of chemical space, being used for visualization, clustering, scaffold-diversity analysis and active-series identification. Built on RDKit and NetworkX, SG integrates scaffold graph analysis into the growing scientific/cheminformatics Python stack, increasing the flexibility and extendibility of the tool compared to existing software.

Introduction (OUP)

ScaffoldGraph (Github)

X-ray structure of the vFLIP-IKKgamma interaction

LigNFam: platform to study Drug-Protein relationships

Scaffold network & tree representations of amodiaquine

AI and Machine Learning

Classification of Protein-Binding sites Using a Spherical Convolutional Neural Network

The analysis and comparison of protein-binding sites aid various applications in the drug discovery process, e.g., hit finding, drug repurposing, and polypharmacology.

Classification of binding sites has been a hot topic for the past 30 years, and many different methods have been published. 

The rapid development of machine learning computational algorithms, coupled with the large volume of publicly available protein–ligand 3D structures, makes it possible to apply deep learning techniques in binding site comparison. 

Our method uses a cutting-edge spherical convolutional neural network based on the DeepSphere architecture to learn global representations of protein-binding sites.

Reference

Scott OB, Gu J and Chan AWE (2022). Classification of Protein-Binding Sites Using a Spherical Convolutional Neural Network. J. Chem. Inf. Model. 62 (22), 5383–5396.

The Drug Discovery Group

Professor David Selwood

Prof. David Selwood
PI: Medicinal Chemistry

Professor Edith Chan

Prof. Edith Chan
PI: Computational Drug Design

Dr Valeria Pingitore

Dr Valeria Pingitore
Postdoc Fellow

Mr Zuhair Elgaid

Mr Zuhair Elgaid
PhD Student

Ms Anastasia Patsiarika

Ms Anastasia Patsiarika
PhD Student

Ms Clara Gathmann

Ms Clara Gathmann
Joint PhD Student

Ms Kate Morling

Ms Kate Morling
PhD Student

Ms Weitong Cynthia Wang

Ms Weitong Cynthia Wang
PhD Student

Mateusz Kaczynski

Mr Mateusz Kaczynski
PhD Student

Oliver Scott

Mr Oliver Scott
PhD Student

Kate Morling and Clara Gathmann collect prizes from UCL's President and Provost, Dr Michael Spence, at the Therapeutic Innovation Network (TIN) event in 2022.

Select publications

  1. Hurley, MJ, Deacon RMJ, Chan AWE, Baker D, Selwood DL & Cogram P (2022). Reversal of behavioural phenotype by the cannabinoid-like compound VSN16R in fragile X syndrome mice. Brain. Vol. 145(1): 76-82.
  2. Radin DP, Caponegro M, Smith G, Moushiaveshi V, Selwood D & Tsirka S (2022). Studies on the function of myeloid-derived Neuropilin-1 in glioma: a focus on tumour hypoxia. FASEB Journal, Vol. 36(51).
  3. Scott OB, Gu J & Chan AWE (2022). Classification of Protein-Binding Sites Using a Spherical Convolutional Neural Network. Journal of Chemical Information and Modeling. J Chem Inf Model. Vol. 62(22): 5383-5396.
  4. Selwood DL, Mota F, Yelland T, Hutton JA, Parker J, et al. (2021). Peptides Derived from Vascular Endothelial Growth Factor B Show Potent Binding to Neuropilin-1. ChemBioChem.
  5. Gregson A, Thompson K, Tsirka SE & Selwood DL (2019). Emerging small-molecule treatments for multiple sclerosis: focus on B cells. F1000Res, 8.
  6. Briggs LC, Chan AWE, Davis CA ... Selwood DL, Collins MK, Barrett TE (2017). IKKγ-Mimetic Peptides Block the Resistance to Apoptosis Associated with Kaposi's Sarcoma-Associated Herpesvirus Infection. J Virol. Vol. 91(23). pii: e01170-17.
  7. Baker D, Pryce G, Visintin C, Sisay S, Bondarenko AI ... Selwood DL (2017). Big conductance calcium-activated potassium channel openers control spasticity without sedation. Br J Pharmacol. Vol. 174(16): 2662-2681.
  8. Prak K, Kriston-Vizi J, Chan AW, Luft C, Costa JR, Pengo N, Ketteler R. Benzobisthiazoles Represent a Novel Scaffold for Kinase Inhibitors of CLK Family Members. Biochemistry. Vol. 55(3): 608-17.
  9. Warne J, Pryce G, Hill JM, Shi X ... Chan AW, Towers GJ, Coker AR, Duchen MR, Szabadkai G, Baker D, Selwood DL (2016). Selective Inhibition of the Mitochondrial Permeability Transition Pore Protects against Neurodegeneration in Experimental Multiple Sclerosis. J Biol Chem. Vol. 291(9): 4356-73.
  1. Miyauchi JT, Chen D, Choi M, Nissen JC, Shroyer KR, Djordevic S, Zachary IC, Selwood D, Tsirka SE (2016). Ablation of Neuropilin 1 from glioma-associated microglia and macrophages slows tumor progression. Oncotarget. Vol. 7(9): 9801-14.
  2. Browne L, Lidster K, Al-Izki S, Clutterbuck L, Posada C, Chan AW, Riddall D, Garthwaite J, Baker D, Selwood DL (2014). Imidazol-1-ylethylindazole voltage-gated sodium channel ligands are neuroprotective during optic neuritis in a mouse model of multiple sclerosis. J Med Chem. Vol. 57(7): 2942-52. Erratum in: J Med Chem. Vol. 58(8): 3637.
  3. Al-Izki S, Pryce G, Hankey DJ, Lidster K, von Kutzleben SM, Browne L, Clutterbuck L, Posada C, Chan AWE ... Selwood DL, Baker D (2014). Lesional-targeting of neuroprotection to the inflammatory penumbra in experimental multiple sclerosis. Brain. 137(Pt 1): 92-108.

  4. Moyes AJ, Khambata RS, Villar I, Bubb KJ ... Selwood DL, Ahluwalia A, Hobbs AJ (2014). Endothelial C-type natriuretic peptide maintains vascular homeostasis. J Clin Invest. Vol. 124(9): 4039-51.

  5. Aldeghi M, Malhotra S, Selwood DLChan AW (2014). Two- and three-dimensional rings in drugs. Chem Biol Drug Des. Vol. 83(4): 450-61.

  6. Rasaiyaah J, Tan CP, Fletcher AJ, Price AJ, Blondeau C, Hilditch L, Jacques DA, Selwood DL et al. (2013). HIV-1 evades innate immune recognition through specific cofactor recruitment. Nature. Vol. 503(7476): 402-405.

  7. Chan AW, Laskowski RA, Selwood DL (2010). Chemical fragments that hydrogen bond to Asp, Glu, Arg, and His side chains in protein binding sites. J Med Chem. Vol. 53(8): 3086-94.

  8. Okuyama M, Laman H, Kingsbury SR, Visintin C, Leo E, Eward KL, Stoeber K, Boshoff C, Williams GH, Selwood DL (2007). Small-molecule mimics of an alpha-helix for efficient transport of proteins into cells. Nat Methods. Vol. 4(2):153-9.

Funding and Partnerships

Logo for Cancer Research UK. A large mosaic C of blue and pink circles plus dark blue text.

Logo for the Brain Research Trust

Wellcome Trust logo

Logo for the Multiple Sclerosis Society UK

Logo for the National Multiple Sclerosis Society

Logo for the British Heart Foundation

Logo for the UKRI Engineering and Physical Sciences Research Council (Green and Navy)

The logo for the URKI Medical Research Council. A quadrilateral, with 'UKRI' over navy on the left, and two teal portions on the right.

Related programmes

Contact Details

David Selwood | Edith Chan
Wolfson Institute for Biomedical Research
The Cruciform Building
University College London
Gower Street
London WC1E 6BT

d.selwood@ucl.ac.uke.chan@ucl.ac.uk