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Cambridge MedChem Consulting

Computational chemistry

The Polypharmacology Browser PPB2

Off-target activity is often ignored and might only be uncovered relatively late in the drug discovery program. Whilst broad spectrum screening is available it can be rather expensive. Predicting potential off-target activities is an attractive approach and this paper describes the development of a prediction tool using nearest neighbours combined with machine learning.

The Polypharmacology Browser PPB2: Target Prediction Combining Nearest Neighbors with Machine Learning DOI

To build PPB2 we collected a bioactivity dataset of all compounds having at least IC50 < 10 uM on a single protein target in ChEMBL22 considering only high confidence data points as annotated in ChEMBL and only targets for which at least 10 compounds were documented

You can try it out here PPB2., depending on the model chosen the results are calculated in a couple of minutes, but don't post your proprietary molecules. Typical results are shown below, clicking on the green "Show NN" button shows the most similar structures.

PPB2results

Pitfalls to avoid when building a Computational Therapeutics Company

 

Everyday I seem to hear about another tech company moving into healthcare, whilst I'm certain that Artificial Intelligence and Machine Learning has the potential to make a significant impact this advice should be compulsory reading for all involved.

https://a16z.com/2018/04/30/building-therapeutics-startups/

How many compounds do you select from virtual screening?

Whilst high-throughput screening (HTS) has been the starting point for many successful drug discovery programs the cost of screening, the accessibility of a large diverse sample collection, or throughput of the primary assay may preclude HTS as a starting point and identification of a smaller selection of compounds with a higher probability of being a hit may be desired. Directed or Virtual screening is a computational technique used in drug discovery research designed to identify potential hits for evaluation in primary assays. It involves the rapid in silico assessment of large libraries of chemical structures in order to identify those structures that most likely to be active against a drug target. The key question is then how many molecules do you select from your virtual screen?

Whilst virtual screening is certainly less expensive than high-throughput screening it is not free, even an in house academic cluster has an overhead (probably equating to > $10,000 per virtual screen). So with that investment how much would you invest in actual compounds?





Virtual Screening Pages Updated

I've updated the pages describing virtual screening, in particular the docking section.

dockedligand

Computational Tools Updated

I've updated the computational tools page in the Drug Discovery Resources.

Predicting bioactivities

Small molecules can potentially bind to a variety of bimolecular targets and whilst counter-screening against a wide variety of targets is feasible it can be rather expensive and probably only realistic for when a compound has been identified as of particular interest. For this reason there is considerable interest in building computational models to predict potential interactions. With the advent of large data sets of well annotated biological activity such as ChEMBL and BindingDB this has become possible.

These predictions may aid understanding of molecular mechanisms underlying the molecules bioactivity and predicting potential side effects or cross-reactivity.

A variety of options are summarised on this page.


Predicting Sites of Metabolism page updated

I've updated the Predicting sites of metabolism page.

Open Source Molecular Modeling

I’ve updated the Computational chemistry page to include a recent excellent publication, Open Source Molecular Modeling DOI a review that categorizes, enumerate, and describe available open source software packages for molecular modeling and computational chemistry.

There is also an online database https://opensourcemolecularmodeling.github.io that covers most aspects of computational drug discovery

Methods
Development Activity
Usage Activity
Cheminformatics
Toolkits
Standalone Programs
Graphical Development Environments
Visualization
2D Desktop Applications (Table [2ddesktopviz])
3D Desktop Applications
Web-Based Visualization
QSAR/ADMET Modeling
Descriptor Calculators
Model Building
Model Application
Visualization
Quantum Chemistry
Ab initio Calcuation
Helper Applications
Visualization
Ligand Dynamics and Free Energy Calculations
Simulation Software
Simulation Setup and Analysis
Virtual Screening and Ligand Design
Ligand-Based
Docking and Scoring
Pocket Detection
Ligand Design

Added to Comp Chem Page


Web browsers used in Drug Discovery

Last week I posted this observation

More and more of the companies/groups that I'm working with are moving away from desktop applications to providing a web-based portfolio of applications for drug discovery. Most seem to use a combination of commercial tools with a selection of in house apps. Whilst this has many advantages it does raise the question about which web browser should they support? Whilst NetMarketshare still has Internet Explorer at 44% this is probably not a good metric to measure browser usage in the Drug Discovery Sector. So for the last couple of months I've been monitoring the web browsers used to access the Drug Discovery Resources since it is unlikely that anyone not interested in drug discovery would spend much time browsing these pages. The results are interesting.

The ranking since 1 Jan 2016 to date is

  1. Chrome 55%
  2. Safari 20%
  3. Firefox 16%
  4. Internet Explorer 4%

Looking at operating systems

  1. Windows 57%
  2. Macintosh 23%
  3. iOS 11%
  4. Android 8%

So the lack users of Internet Explorer is not due to the absence of Windows users. This must have implications for all developers, the users appeared to have moved to the more modern web browsers.

Update

I've now data from around 10 different sites involved in drug discovery or software/databases to support drug discovery, ranging from small sites with about 10,000 hits a month to major sites with many millions of hits a month, and I've now included the average data in the table below.

webbrowsers

It looks like the data from Drug Discovery Resources reasonably reflects the usage in the Drug Discovery sector.

Web-based tools

More and more of the companies/groups that I'm working with are moving away from desktop applications to providing a web-based portfolio of applications for drug discovery. Most seem to use a combination of commercial tools with a selection of in house apps. Whilst this has many advantages it does raise the question about which web browser should they support? Whilst NetMarketshare still has Internet Explorer at 44% this is probably not a good metric to measure browser usage in the Drug Discovery Sector.

So for the last couple of months I've been monitoring the web browsers used to access the Drug Discovery Resources since it is unlikely that anyone not interested in drug discovery would spend much time browsing these pages. The results are interesting.

The ranking since 1 Jan 2016 to date is

  1. Chrome 56%
  2. Safari 20%
  3. Firefox 16%
  4. Internet Explorer 4%

Looking at operating systems

  1. Windows 57%
  2. Macintosh 23%
  3. iOS 11%
  4. Android 8%

So the lack users of Internet Explorer is not due to the absence of Windows users. This must have implications for all developers, the users appeared to have moved to the more modern web browsers.

Update

A number of readers/companies have contacted me since I published with broadly similar results, I hope to compile and publish the anonymised results next week.

Medicinal Chemistry Toolkit app

A review of the Medicinal Chemistry Toolkit app for iOS

http://www.macinchem.org/reviews/mctk/medchemtoolkit.php

Worth a look.

The a third edition of the popular book, The Organic Chemistry of Drug Design and Drug Action by Silverman and Holladay has just been released, I’ve added it to the book list.

Vortex users might be interested in a new script that implements an interesting paper from Wagner et al Moving beyond Rules: The Development of a Central Nervous System Multiparameter Optimization (CNS MPO) Approach To Enable Alignment of Druglike Properties DOI that describes an algorithm to score compounds with respect to CNS penetration.

Lilly MedChem rules can now be installed using Homebrew. In late 2012 Robert Bruns and Ian Watson published a paper entitled Rules for Identifying Potentially Reactive or Promiscuous Compounds DOI. This article describes a set of 275 rules, developed over an 18-year period, used to identify compounds that may interfere with biological assays, allowing their removal from screening sets.