ChEMBL

Books and Papers - 5 - Time Warps, String Edits, and Macromolecules: The Theory and Practice of Sequence Comparison

You know what it's like - you have a deadline, stuff that's really important to do, you get your work area ready, and then you browse your bookcase for something interesting. Four hours later, it's time to do something else. Well that was yesterday, and I spent those hours re-reading this old classic. Fairly recently released in a reprinted, and cheaper form. In my opinion, this is one of the best books in sequence comparison, it is full of interesting ideas, has good coverage of related fields of computer science, and a coverage of the algorithms that are deep enough to allow you to go away and start messing around with code.

%D 2000
%E David Sankoff & Joseph Kruskal
%T Time Warps, String Edits, and Macromolecules: The Theory and Practice of Sequence Comparison
%I Cambridge University Press
%O ISBN 978-1575862170

EMBL-EBI Industry Programme

I thought I would post a note on the EMBL-EBI's Industry Programme. This is a forum open to all life-science companies to network and understand the tools, resources and direction of the EMBL-EBIs activities, and also encourage discussion of pre-competitive and collaborative activities between life-science companies. Given the increasing demands for cost-reduction, data integration and knowledge representation within the sector this activity is becoming increasingly important. Details of how to join the can be found on the EMBL-EBI web-site (link above). An analogous group exists for smaller companies (SME/SMBs).

ChEMBL Specialist Blogs

We have set-up some specialist sub-blogs to the ChEMBL blog - ChEMBL-grants, and ChEMBL-curators. This is for open exchange of information, and will cover research proposals, beta-testing of functionality, will cover some of the minutiae of the curation pipeline, discuss methods and curation strategies, etc. etc.

PhD Student Projects within ChEMBL

Here are details of some of the PhD studentship project ideas for the ChEMBL group. If you are interested in studying in any of these areas at the EMBL-EBI outstation in Hinxton, please contact us. The underlying theme of the projects is to provide infrastructure components built upon the ChEMBL databases for applied and translational drug discovery. They all offer the opportunity to study and develop cutting-edge Open Source drug discovery technologies in a highly collaborative, diverse and international setting.

1. Non-human Secreted Proteins as New Therapies.

Surprisingly, several classes of very important human biological therapeutics are derived from non-human sources; for example, hirudin from medicinal leaches. This project will apply data-mining approaches to characterise the features for immunotolerance on non-host proteins, and then develop a series of approaches to identify potential candidate therapeutic proteins from a wide variety of organisms (e.g. Mammals, Ticks, Flukes, Nematodes, etc.). The project will integrate sequence and structure-based data mining methods along with KDD/data-mining methods to predict function, pharmacokinetic and affinity properties.

2. Monoclonal Antibody Drug ‘Rescue’

Monoclonal antibody drugs (mAbs) are viewed as highly specific therapies, with low clinical failure rates. However, attrition for mAb therapies is often expensive and occurs at a late and expensive stage in their clinical progression, with success often crucially dependent on choice of disease model and trial design. As part of our CandiStore project, we have accumulated a unique set of clinical stage mAbs, and their targets ligands. This project will apply modelling, docking, text-mining and KDD approaches to understand and predict new clinical applications of previously failed mAbs. The project will also attempt to discover general features for success/failure of this important class of therapy.

3. Automated Drug Design (‘Robot-Chemist’)

The discovery and optimisation of novel, well tolerated drugs is becoming an increasingly important commercial challenge. We have assembled a large training set of SAR data in our StARlite database, and have produced proof-of-principle applications in areas such as bioisostere discovery, affinity optimisation, etc. This project will build a catalog of empirically observed and synthetically tractable transformations from a given chemical starting point, and attempt to objectively score their likely effect on bioactivity, in particular drug like properties such as metabolism, frank toxicity, absorption, etc. This project will provide an excellent introduction to the principles of medicinal chemistry from a compound design perspective, and also a firm grounding in a broad variety of KDD approaches.

4. Drug Design Strategies for Robustness to Acquired Resistance.

Acquired resistance, the selection of mutant forms of a target under the selective pressure of a cidal drug, is of increasing importance in both anti-microbial and anti-cancer targeted therapies. In the vast majority of cases, this resistance can be understood at a structural level, once the 3-D structure of the drug-target complex is established. This project will provide an integrative approach for the prediction of alternate functional forms of a target, under simulated evolutionary pressure of drug binding. Techniques such as comparative modelling, sequence analysis, Monte-Carlo simulation and QSAR approaches will be applied, and the methods then used at genome scale to identify targets and compound design strategies likely to be robust to acquired resistance. Depending on progress made during the major part of the project, the methods could be applied to understand differential drug response caused by genetic diversity/cSNPs in the human genome for currently approved therapies.

CandiStore - An Overview

A few people have mailed me about getting hold of information on 'failed' drugs, or drugs in clinical development. This is one of those things that sounds really simple, should be readily available but isn't. However, such a list would be really useful in many applications in life science informatics, for example in understanding or anticipating the chemotypes of drug failure, to provide data for second or third generation agents with differentiated profiles (MeToo's are not all bad you know!), to perform 'drug rescue' studies (i.e. in this context to find a new clinical indication for a drug outside of it's originally anticipated use). There are some interesting commercial options for this type research, even for 'off-patent' drugs that can lead to both commercial gain, and significant patient benefit.

For the case of a drug that has been withdrawn post approval, it is quite trivial to get hold of a list of these, it is however, more difficult to get hold of reasons or data for the withdrawl. There are arguably two fundamental reasons for withdrawl, Safety, or Commercial, and both of these words have potent meaning in the Pharmaceutical Business. Do not even think of getting a clear view on the reasons for failure for compounds in development.

Some time ago we started to analyse affinity data of drugs against targets other than their conventional target, and this led to the collection on an ad hoc basis of clinical development candidates against particular targets or target classes. Doing this on a couple of different systems led to a search strategy that makes, in our view, the collection of a complete list of clinical stage development candidates for deposition in the public domain a possibility. This database we call CandiStore, it attempts to capture....

InChIs/SMILES for StARlite database

The InChIs and SMILES for almost all of the current StARlite (release 31) set of compounds is now available. Please do not upload the structures into public domain search engines or registries, since it is bound to lead to confusion later on, when full data ChEMBL data is registered. Thanks to the white hatted Jeremy Besnard for the file conversion, while I get my PipeLine Pilot properly set up.....

Please, please, please, if you click the mail link above, do not edit the subject string of the message ;)

Recruitment Closing Date Approaching

Posting from my sick bed, a reminder that the closing deadline for applications for most of the positions currently available is Sunday the 8th of February.

Fantasy Pharma - The Game

The Drug Discovery industry is in a 'bit of a state', as they say. A common complaint is that the fault is that of current management, and if that only the right decisions were taken, everything would be fine. So why don't we run an experiment - but in a game format. The basic idea will be to become a CEO of a virtual pharma, you can select some drugs, and track them through to the market. You will start in a pretty good position with two launched revenue generating products, let's see how you get on. The winner will be the person at the end of the game with the largest pile of cash. This cash is virtual, of course, it is just a game.

Here are some preliminary rules.