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Cambridge MedChem Consulting

Drug Discovery Resources Updated

I've spent a little time updating the Drug Discovery Resources Section of the website. In particular:

halogenbindingcomparison

Drug Discovery Resources Updated

I've updated the Bioisosteres section adding a few more examples of aryl ring bioisosteres, and I've added CypReact to the predicting metabolism page.

arylNbioisostere

Drug Discovery Resources Updated

I've made a few additions and updated to the Drug Discovery Resources pages. In particular I've updated the covalent inhibitors page and added additional examples to the molecular interactions page. I've also started updating the ADME section and added a page on half-life and how it might be modulated.

repeated

Updated brain penetration page

I've updated the brain penetration page to include data from a recent publication, Small Molecule Kinase Inhibitors for the Treatment of Brain Cancer DOI which discusses the issues with targeting brain and central nervous system cancers.

macrolisation

Predicting Sites of Metabolism page updated

I've updated the Predicting sites of metabolism page.

Solubility

I’ve just updated the page on solubility and added a couple of useful assay references.

Solubility may also have an impact on preclinical assays, limited solubility in preclinical ADMET assays may give a false impression of the compounds profile in in vitro assays. Many of the false positives seen in Fragment-based screening are thought to be due to poor solubility at the high concentrations used in the screen. Perhaps the most important is the impact poor solubility can have on gastrointestinal absorption it may also preclude other routes of administration (intravenous).

Using 3Dmol.js

The Drug Discovery Resources pages are intended to act as a resource for scientists undertaking drug discovery, they were initially based on a course I give but have been expanded to give much more detail and to cover subjects not covered in the course. The other advantage of an online resource is that I can include features not possible in static pages.

I had started to include interactive structures a while ago but the problems with java applets and plugins meant I had to abandon that effort. The recent advances in javascript viewers has opened up new possibilities and I've started to reinvestigate more interactive viewers. The initial work uses the fantastic molecule viewer 3Dmol.js developed by David Koes.

3Dmol.js is a modern, object-oriented JavaScript library that uses the latest web technologies to provide interactive, hardware-accelerated three-dimensional representations of molecular data without the need to install browser plugins or Java. 3Dmol.js provides a full featured API for developers as well as a straightforward declarative interface that lets users easily share and embed molecular data in websites.

You can read more about it here DOI.

The first page to include an interactive structure is Aldehyde Oxidase, the PDB structure 4UHW is interesting because it shows the binding of both a substrate and an inhibitor binding at a site remote from the active site.

I hope you find this useful and please feel free to contact me with comments and/or suggestions.

Predicting sites of metabolism

I have updated the drug discovery resources on predicting sites of metabolism, I've added several new tools and web-based resources.

Aldehyde Oxidase

I have updated the drug discovery resources page on Aldehyde Oxidase. In particular I have included more detail on the species differences and added the recent X-ray structure of AOX1 with substrate and inhibitor bound.

Insects in Drug Discovery

The company N2MO offers the use of insects as model organisms. They can be used for ADME screening in particular brain penetration studies.

The Grasshopper: A Novel Model for Assessing Vertebrate Brain UptakeOlga Andersson, Steen Honoré Hansen, Karin Hellman, Line Rørbæk Olsen, Gunnar Andersson, Lassina Badolo, Niels Svenstrup, and Peter Aadal Nielsen EntomoPharm R&D, Medicon Village, Lund, Sweden (O.A., K.H., G.A., P.A.N.); Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (S.H.H., L.R.O.); and Division of Discovery Chemistry and Drug Metabolism and Pharmacokinetics, H. Lundbeck A/S, Copenhagen, Denmark (L.B., N.S.) Received April 10, 2013; accepted May 10, 2013

ABSTRACT The aim of the present study was to develop a blood-brain barrier (BBB) permeability model that is applicable in the drug discovery phase. The BBB ensures proper neural function, but it restricts many drugs from entering the brain, and this complicates the development of new drugs against central nervous system diseases. Many in vitro models have been developed to predict BBB permeability, but the permeability characteristics of the human BBB are notoriously complex and hard to predict.

Consequently, one single suitable BBB permeability screening model, which is generally applicable in the early drug discovery phase, does not yet exist. A new refined ex vivo insect-based BBB screening model that uses an intact, viable whole brain under controlled in vitro-like exposure conditions is presented.

This model uses intact brains from desert locusts, which are placed in a well containing the compound solubilized in an insect buffer. After a limited time, the brain is removed and the compound concentration in the brain is measured by conventional liquid chromatography-mass spectrometry. The data presented here include 25 known drugs, and the data show that the ex vivo insect model can be used to measure the brain uptake over the hemolymph-brain barrier of drugs and that the brain uptake shows linear correlation with in situ perfusion data obtainedinvertebrates.Moreover,this study shows that the insect ex vivo model is able to identify P-glycoprotein (Pgp) substrates, and the model allows differentiation between low-permeability compounds and compounds that are Pgp substrates.

Metrabase

p>The Metabolism and Transport Database (Metrabase) is a cheminformatics and bioinformatics resource that contains curated data related to human small molecule metabolism and transport, Journal of Cheminformatics 2015, 7:31 DOI. Currently it includes interaction data on 20 transporters, 3438 molecules and 11649 interaction records manually abstracted from 1211 literature references and supplemented with data from other resources as shown in the image below taken from the original publication.

s13321-015-0083-5-1

I've added this and more details to the Transporters page of the Drug Discovery Resources

CYP Interactions

Prediction of Cytochromes P450 Inhibition, Bioinformatics, 2013, 29, 2051-2052 WhichCyp, a tool for prediction of which cytochromes P450 isoforms (among 1A2, 2C9, 2C19, 2D6 and 3A4) a given molecule is likely to inhibit. The models are built from experimental high-throughput data using support vector machines and molecular signatures.

Drug Discovery Resources Updates

I’ve added two new pages to the ADME section, there are now separate pages for CYP2D6 inhibitors and CY3A4 inhibitors.

22 July 2014 Updated to include CYP2C9 and CYP2C19 inhibitors.

Nheterocycles

Aldehyde Oxidase page updated

I’ve updated the page on Aldehyde Oxidase, an enzyme in metabolism of a wide variety of nitrogen heterocycles.

I’ve also included A recent publication DOI that suggests a simple test for the early identification of heteroaromatic drug candidates that have a high probability of metabolism by AO. Bis(((difluoromethyl)sulfinyl)oxy)zinc (DFMS) was used as a source of the CF2H racial, simple LCMS was then used to identify a characteristic M+50 peak. It is also possible to scale up and isolate these metabolically blocked compounds and retest them for improved qualities.

A review of FAst MEtabolizer (FAME)

Whilst much computational work is undertaken to support, library design, virtual screening, hit selection and affinity optimisation the reality is that the most challenging issues to resolve in drug discovery often revolve around absorption, distribution, metabolism and excretion (ADME). Whilst we can measure the levels of parent drug in various medium tracking metabolic fate can often be a considerably more difficult proposition requiring significant resources. For this reason prediction of sites of metabolism has become the subject of current interest.

FAME DOI is a collection of random forest models trained on a comprehensive and highly diverse data set of 20,000 small molecules annotated with their experimentally determined sites of metabolism taken from multiple species (rat, dog and human). In addition dedicated models are available to predict sites of metabolism of phase I and II processes.

aspirinFame

FAME offers a high performance prediction of sites of metabolism mediated by a wide variety of mechanisms.

The full review is available here

Plasma Protein Binding

I’ve just updated the section on distribution and plasma protein binding in the Drug Discovery Resources.

Suggested Books

I’ve just updated the list of suggested books.

Included books on bioisosteres and fragment-based screening.



SMARTCyp 2.4 released

The new SMARTCyp version 2.4 includes solvent accessible surface area (SASA) in the scoring function. SASA is computed using the 2DSASA algorithm from 2D coordinates.

smartcyp

  A paper describing the new models and their predictive accuracy on nine CYP isoforms is available in Molecular Pharmaceutics DOI

Drug Discovery Resources Update

I’ve updated the Drug Discovery Resources Pages over the Christmas Break. In particular I’ve updated the Fragment Based Screening section and added a page on building a fragment collection. I’ve also updated the section on CYP interactions, expanding the Induction section.

SMARTCyp Updated

SMARTCyp 2.3 has been released with some additional improvements including: Improved energies for N-oxidations Empirical correction for unlikely N-oxidations of tertiary alkylamines A filtering functionality for excluding compounds with very low activation barriers to CYP-mediated oxidations A smiles string can now be input directly on the command line using the -smiles flag.   Available as usual at http://www.farma.ku.dk/smartcyp   The science behind the improved N-oxidations and the empirical correction has also been published in a paper in Angewandte Chemie: DOI  

CYP450 Induction

I’ve just finished updating the CYP450 interactions of the Drug Discovery Resources, in particular I expanded the section on CYP450 enzyme induction.

Updated Aldehyde Oxidase page

I’ve updated the page on Aldehyde Oxidase (AOX1), an enzyme involved in the metabolism of many nitrogen containing heterocycles.

Aldehyde Oxidase

I’ve added a section on Aldehyde Oxidase (AOX1), an enzyme involved in the metabolism of many nitrogen containing heterocycles.

Updated Reading List

Cyprotex ADME Guide: An excellent guide to understanding and interpreting ADME assays and results, available on request from the Cyprotex home page.