Tackling drug resistance

Project Details

On-going technological advancements have led to dramatic increases in the amounts of biological data being generated. Along with the evolution of high performance computing and computational tools, this has provided us with a wealth of information, analytical power and the opportunity to investigate fundamental health and biotechnological problems of a different magnitude and kind, complementary to and able to guide conventional approaches. Our group is interested in developing and experimentally validating novel computational methods to exploit this data, enhancing the impact of genome sequencing, structural genomics, and functional genomics on biology and medicine.

One of our main areas of interest is in the development of predictive and analytical tools and databases to investigate and understand the relationship between protein sequence, structure and function and phenotype, allowing us to gain unique insights into:

  • The molecular basis of genetic diseases, including cancer;
  • Understanding the molecular mechanisms behind drug resistance, to guide personalized patient treatment and the development of resistance resistant drugs;
  • Evolutionary insights derived from the analysis of protein structure and function;
  • Small molecule activity and toxicity as an aid to the design of novel drugs.

Keywords: Machine learning, databases, mutations, genetic disease, drug resistance, cancer, molecular mechanism, homology modelling, protein structure and function, small molecules, drug development.

We have developed and host a wide range of widely used and freely-available tools, including:

  • Arpeggio: Calculation and visualisation of all molecular interactions.
  • mCSM-Stability: Predicting effects of mutations on protein stability.
  • DUET: An integrated method for predicting effects of mutations on protein stability.
  • mCSM-PPI (http://bleoberis.bioc.cam.ac.uk/m: Predicting effects of mutations on the affinity of protein-protein interactions.
  • mCSM-AB: Predicting effects of mutations on antibody-antigen binding affinity.
  • mCSM-NA: Predicting effects of mutations on the affinity of protein-nucleic acid interactions.
  • mCSM-lig: Predicting effects of protein mutations on affinity for small molecules.
  • CSM-lig: Predicting the protein binding affinity of small molecules.
  • KAMP: Identification of protein kinase activating mutations.
  • pkCSM: Predicting small molecule pharmacokinetic and toxicity properties.
  • Platinum DB: Structural database of experimentally measured effects of missense mutations on protein-ligand complexes.
  • TROMBONE DB: Optimisation of Botulinum and Tetnus neurotoxins for medicinal purposes.
  • Symphony DB: Classification of VHL missense mutations according to risk of clear cell Renal carcinoma.

Researchers

Dr David Ascher, Group Leader

Dr Douglas Pires (Fiocruz-Minas)

Amanda Tábita da Silva Albanaz, Undergraduate Research Student (PROBIC - Fapemig, Brazil), CNPq, co-supervised with Douglas Pires

Collaborators

Professor Sir Tom Blundell, University of Cambridge

Professor Taane Clark, London School of Hygiene & Tropical Medicine

Dr Nick Furnham, London School of Hygiene & Tropical Medicine

Dr Katerina Artavanis-Tsakonas, University of Cambridge

Professor Véronique Dartois, Public Health Research Institute Center

Professor Taís Nóbrega de Sousa, Fiocruz-Minas

Professor Alexandre Machado, Fiocruz Minas, Brazil

Professor Rubens Neto, Fiocruz Minas

Funding

Newton Fund/MRC: "Understanding Antimicrobial Resistance Mutations in Tuberculosis: Towards Personalised Treatment to Combat Multi‐drug Resistance."

Jack Brockhoff Foundation Grant: “Understanding the Molecular Mechanisms of Complex Mutations”.

Research Opportunities

This research project is available to PhD students to join as part of their thesis.
Please contact the Research Group Leader to discuss your options.

Research Publications

  1. Phelan J, Coll F, McNerney R, Ascher DB, Pires DE, Furnham N, Coeck N, Hill-Cawthorne GA, Nair MB, Mallard K, Ramsay A, Campino S, Hibberd ML, Pain A, Rigouts L, Clark TG.  Mycobacterium tuberculosis whole genome sequencing and protein structure modelling provides insights into anti-tuberculosis drug resistance. BMC Medicine 2016; 14: 31.
  2. Pires DEV, Blundell TL, Ascher DB. mCSM-lig: quantifying the effects of mutations on protein-ligand affinity in genetic disease and the emergence of drug resistance. Scientific Reports 2016; 6: 29575.
  3. Pires DEV, Chen J, Blundell TL, Ascher DB. In silico functional dissection of saturation mutagenesis: Interpreting the relationship between phenotypes and changes in protein stability, interactions and activity. Scientific Reports 2016; 6: 19848.
  4. Silvino ACR, Costa GL, de Araujo FCF, Ascher DB, Pires DEV, Fontes CJF, Carvalho LH, de Brito CFA, de Sousa TN.  Variation in human cytochrome P-450 drug-metabolism genes: a gateway to understand Plasmodium vivax relapses. PLOS One 2016; 11: e0160172.
  5. Ascher DB, Wielens J, Nero TL, Morton CJ, Parker MW. Potent hepatitis C inhibitors bind directly to NS5A and reduce its affinity for RNA. Scientific Reports 2014; 4: 4765.

Research Group

Ascher laboratory: Structural biology and bioinformatics



Faculty Research Themes

Infection and Immunology

School Research Themes

Infection & Immunity, Molecular Mechanisms of Disease, Therapeutics & Translation



Key Contact

For further information about this research, please contact the research group leader.

Department / Centre

Biochemistry and Molecular Biology