University of Dundee

Professor Andrew Hopkins FRSC

Chemoinformatics, chemogenomics and drug discovery
Position: 
Chair of Medicinal Informatics and SULSA Research Professor of Translational Biology
Address: 
College of Life Sciences, University of Dundee, Dundee
Full Telephone: 
+44 (0) 1382 381010, int ext 81010

Research

We develop and experimentally validate innovative concepts in drug discovery and design, including:

Automated, adaptive, de novo drug design
In silicopolypharmacology profiling and design
Multi-objective prioritization of compounds
Genome-scale drug target identification and prioritization 
Biosensor analysis of GPCRs
Biophysical fragment screening of membrane and soluble proteins. 

Our research activities focus on developing novel informatics and experimental methods to enable new, more effective, ways of conducting drug discovery. My laboratory consists of a Medicinal Informatics group, that uses chemoinformatics, structural bioinformatics, database and and machine learning techniques in its research and a Biosensor Screening Lab, headed by Dr Iva Navratilova, that specializes in biosensor technologies. Our goal is to develop novel methods and exploit them in real drug discovery programs. A summary of our current research interests is found below:

Chemogenomics

The growing number of available genome sequences of pathogens allows, for the first time, the opportunity to rationally prioritize all potential drug targets for a wide range of emerging and neglected infectious diseases. Despite the fact that our knowledge of observed attributes of the vast majority of pathogen proteins is limited or missing, our research is aimed at developing methods to prioritized potential drug targets from a pathogen genome a priori by inference from the collective wealth of bio-pharmacology knowledge available, such as genome sequences, model organism knock-outs, protein structures, medicinal chemistry structure-activity data and literature abstracts. We have applied our approach to created systems that enable the identification and prioritization of drug targets from the pathogenic, gram-negative bacteria, Pseudomonas aeruginosa (Aeropath Targets Database) and the genomes of the causative agents of several important tropical diseases including African trypanosomiasis (sleeping sickness), Chagas disease and Leishmaniasis (Kinetoplastid Target Database). Our mission is to develop chemogenomics systems that enable the rapid analysis of pharmacologyfor any genome.

Adaptive Drug Design

The clinical efficacy and safety of a drug is determined by its activity profile across multiple proteins in the proteome. However, designing drugs with a specific multi-target profile is a complex and difficult task. We are exploring new methods to discover and rationally design of compounds against polypharmacology (multi-target) profiles. Therefore methods to rationally design drugs a priori against profiles of multiple proteins would have immense value in drug discovery.  We are developed methods to automate drug design. We are developing in silico approaches that that mimic the creativity of medicinal chemists by using evolutionary optimization methods. We collaborate with experimentalist to synthesis and test the compounds designed by the algorithms. The approach can be a useful source of drug leads where multi-target profiles are required to achieve either selectivity over other drug targets or a desired polypharmacology.

Biosensor-based Drug Discovery

Our experimental laboratory research is focused on developing new biophysical screening methods for efficient drug discovery. We are developing biosensor based screening methods that enable us to characterise the kinetics and thermodynamics of molecular interactions. The binding kinetics of an interaction determine the affinity of a drug to its target and can impact the coupling efficiency of the drug by affecting the state of equilibrium. Therefore understanding the binding kinetics can help shape the clinical profile of a drug that are important to patients: efficacy, safety, duration of action, greater tolerability, indication and therapeutic differentiation. The sensitivity and throughput of the new generation of surface plasmon resonance (SPR) instrumentation enables this technology to be used for screening of large libraries of fragments or compounds. In particular our research is currently focused on:

Developing the application of biosensor screening to membrane proteins, such as G-protein coupled receptors.
Development of SPR-based fragment screening
SPR as a method for multi-target screening

For further information on the Biosensor Laboratory’s research please see the staff page of Dr Iva Hopkins Navratilova.

 

 

 

Publications

  1. The role of ligand efficiency measures in drug discovery. Hopkins, A.L., Kereru, G.M., Leeson, P.D., Rees, D.C. and Reynolds, C.H. Nature Reviews Drug Discovery, 2013 (accepted).
  2. Discovery of b-adrenergic receptor ligands using biosensor fragment screening of tagged wild-type receptor. Aristotelous, T., Ahn, S., Shukla, A.K., Gawaron, S., Sassano, M.F., Kahsai, A.W., Wingler, L.M., Zhu, X., Tripathi-Shukla, P., Huang, X.-P., Riley, J., Besnard, J., Read, K.D., Roth, B.L., Gilbert, I.H., Hopkins, A.L., Lefkowitz, R.J. and Navratilova, I. ACS Med.Chem.Letts 2013, (4 (10), 1005-1010).
  3. De novo design of ligands against multi-target profiles. Besnard, J. and Hopkins, A.L. In De Novo Molecular Design, Ed: Gisbert Schneider, Wiley, 2013.
  4. Automated design of ligands to polypharmacological profiles. Jérémy Besnard, Gian Filippo Ruda, Vincent Setola, Keren Abecassis, Ramona M. Rodriguiz, Xi-Ping Huang, Suzanne Norval, Maria F. Sassano, Antony I. Shin, Lauren A. Webster, Frederick R.C. Simeons, Laste Stojanovski, Annik Prat, Nabil G. Seidah, Daniel B. Constam, G. Richard Bickerton, Kevin D. Read, William C. Wetsel, Ian H. Gilbert, Bryan L. Roth and Andrew L. Hopkins, Nature, (2012)492, 215–220 doi:10.1038/nature11691