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Cambridge MedChem Consulting

Developing an assay for high-throughput screening

SULSA’s Assay Development Fund is actively recruiting innovative molecular targets for which there is a strong rationale for therapeutic potential.

Development of a high-throughput assay provide access to the various drug discovery initiatives that are available to the academic community, i.e. MRC DPFS, Bayer G4Targets, Wellcome Trust translational fund, the European Lead Factory, AZ innovation portal etc.

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

Privileged Structures

The term "privileged structures" was first coined by Ben Evans DOI who recognised the potential of certain regularly occurring structural motifs as templates for derivatization to discovery novel ligands for binding to proteins. Such motifs are of course distinct from false positives molecules that appear in multiple screens due to assay interferences.

A recent publication describes a related approach looking for multi target ligands, a systematic analysis of currently available X-ray structures for compounds forming complexes with different targets DOI, by using X-ray structures they aim to avoid molecules that might interfere with the assay, some of these ligands were described in the medicinal chemistry literature, making it possible to consider additional target annotations and search for analogues. This work identified 133 unique analogue-series-based scaffolds were isolated that can serve as templates for the design of new compounds with multitarget activity.

I've added this to the Privileged Structures page of the Drug Discovery Resources.




D3R Grand Challenge 2: blind prediction of protein–ligand poses, affinity rankings, and relative binding free energies

The Drug Design Data Resource (D3R) is an NIH-funded resource dedicated to improving method development in ligand docking and scoring through community-wide blinded prediction challenges (http://www.drugdesigndata.org). DOI

The Drug Design Data Resource (D3R) ran Grand Challenge 2 (GC2) from September 2016 through February 2017. This challenge was based on a dataset of structures and affinities for the nuclear receptor farnesoid X receptor (FXR), contributed by F. Hoffmann-La Roche. The dataset contained 102 IC50 values, spanning six orders of magnitude, and 36 high-resolution co-crystal structures with representatives of four major ligand classes. Strong global participation was evident, with 49 participants submitting 262 prediction submission packages in total. Procedurally, GC2 mimicked Grand Challenge 2015 (GC2015), with a Stage 1 sub-challenge testing ligand pose prediction methods and ranking and scoring methods, and a Stage 2 sub-challenge testing only ligand ranking and scoring methods after the release of all blinded co-crystal structures. Two smaller curated sets of 18 and 15 ligands were developed to test alchemical free energy methods. This overview summarises all aspects of GC2, including the dataset details, challenge procedures, and participant results. We also consider implications for progress in the field, while highlighting methodological areas that merit continued development. Similar to GC2015, the outcome of GC2 underscores the pressing need for methods development in pose prediction, particularly for ligand scaffolds not currently represented in the Protein Data Bank (http://www.pdb.org), and in affinity ranking and scoring of bound ligands.

Conclusions:

  • Successful prediction of ligand–protein poses depends on the entire workflow, including factors extrinsic to the core docking algorithm, such as the conformation of the protein selected.
  • The accuracy of pose predictions tends to be improved by the use of available structural data, via ligand overlays and/or selection of receptor structures solved with similar ligands.
  • The accuracy of the poses used in structure-based affinity rankings does not clearly correlate with ranking accuracy.
  • Explicit solvent free energy methods did not, overall, pro-vide greater accuracy than faster, less detailed scoring methods

Selecting hits 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?

The results of a virtual screening run are effectively a rank ordering of the virtual screening deck ordered by whatever scoring function(s) that have been used. The task then becomes selection of molecules for experimental determination of activity.

I posed this question on the website and the results are shown below. Whilst this obviously a limited snapshot it is interesting that there is a wide variety of responses.

screening

I've included the results on the page on Selecting Compounds from a Virtual Screening Run.

Trust but verify

There is an article in Nature describing a collection of problems that have arisen from incorrect chemical structures in biological screens DOI. I'm slightly surprised that this is regarded as newsworthy, but I guess it serves as a timely reminder.

The data from screening campaigns invariably contains errors

  • It is often a single point assay
  • Quality and diversity of Sample Collection is variable
  • Compounds may interfere with the detection system
  • False positives due to aggregation
  • High density plates can result in cross contamination, edge effects

There is a very simple mantra you should adopt when analysing screening data "Trust but verify".

  • Check compounds that were found active against the selected target are re-tested using the same assay conditions used during the HTS.
  • Does a resynthesised (not repurchased) show the same activity
  • Dose response curve generation: an IC50 or EC50 value is then generated, does it have a reasonable slope? Uneffected by incubation time.
  • Are related analogues available, check for genuine Structure-Activity Relationships

elf

There is a strategy for the analysis of HTS data in the Drug Discovery Resources.

MRC opens drug discovery funding applications

The Medical Research Council (MRC) recently announced that it will provide funding for up to ten high throughput screening (HTS) projects a year to run within the AstraZeneca UK Centre for Lead Discovery. The centre is home to NiCoLa-B, the world’s the world's most advanced drug discovery robot. NiCoLa-B can test up to 300,000 compounds a day

Closing date is 27 Sept 2017

https://www.mrc.ac.uk/funding/browse/mrc-az-cld/mrc-astrazeneca-centre-for-lead-discovery/.

Further information on the collaboration with AstraZeneca

Virtual Screening Pages Updated

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

dockedligand

European Lead factory "Hit to Lead" workshop

The European Lead Factory hold annual meetings intended to support early career scientists, this years meeting will focus on "Hit to Lead optimisation". The meeting will be held at Janssen Pharmaceutica NV, Beerse, Belgium, November 6th - 7th 2017.

Full details are here https://www.europeanleadfactory.eu/early-career-researcher-event/.

Free participation (incl. reimbursement of travel costs up to € 250, accommodation, access to the social get-together) at the conference.

The draft agenda is here.

A great opportunity for those just starting on their drug discovery career.

Fragment Screening - XChem at Diamond

Fragment-based screening has become increasingly popular over the last 10 years and has proven to be a viable alternative to high-throughput screening. The appeal has been driven by several features

  • “Fragment Space” is smaller than “Chemical Space” and can be more effectively probed with a relatively small library
  • A million compounds cover only a small fraction of the suggested 1060 Chemical Space, whilst 2000 compounds can probe much of the 106 Fragment Space
  • Protein requirements should be smaller
  • Binding Efficiency for small molecules is likely to be higher
  • Hit rates for Fragment-based screening appear to be higher, typically 3-10%.

Whilst there are a number of biophysical methods used for Fragment-based screening structural information is often a critical step in moving the programme forward. X-ray crystallography is a very powerful technology for use in converting a "hit" into a lead for drug discovery. However, the experimental overheads have historically been too high for it to be widely used for primary screening. The X-Chem project at Diamond aims to make the technology more widely accessible.

At Diamond beamline I04-1, the full X-ray screening experiment has now been implemented as a highly streamlined process, allowing up to 1000 compounds to be screened individually in less than a week (including 36 hours' unattended beamtime). The process covers soaking, harvesting, automatic data collection, and data analysis; fragment libraries are available, though users can bring their own.

An overview of the process is available here in practice, users must generate the crystals in their home lab, and are required to come and perform soaking and harvesting themselves. Users do not need to be present for the X-ray data collection when data is collected automatically. Data analysis builds on the existing automatic data processing, and they have developed tools to streamline density interpretation and refinement (PanDDA and XChemExplorer). Use of these tools at Diamond is optional but highly recommended.

Whilst users are free to bring their own libraries a number of libraries are also available these include the Maybridge 1000, Edelris fragments, and Diamond-SGC Poised Library (DSPL), a fragment library designed to allow rapid, cheap follow-up synthesis to provide quick SAR data. The calculated physicochemical properties of the DSPL fragment collection are shown below.

test10png

For more details on the design of the library O. B. Cox, K. Krojer, P. Collins, O. Monteiro, R. Talon, A. Bradley, O. Fedorov, J. Amin, B. D. Marsden, J. Spencer, F. von Delft, P. E. Brennan, A poised fragment library enables rapid synthetic expansion yielding the first reported inhibitors of PHIP(2), an atypical bromodomain. Chem. Sci.,2016. 7: p. 2322-2330 DOI.

There is more information in this podcast https://www.ndm.ox.ac.uk/frank-von-delft-x-rays-for-drug-discovery

The European Lead Factory Works!

The European Lead Factory (ELF) is a collaborative public-private partnership aiming to deliver novel lead molecules for drug discovery programs. When the consortium was formed around 5 years ago there was a lot of scepticism about whether a group of 30 partners rating from large Pharma companies to small academic groups could ever agree on a legal framework that would allow the ELF to function. In a addition, in an industry where confidentiality was critical to maintaining intellectual property the idea that a group of large Pharma companies would share their sample collections often regarded as the "Crown Jewels" seemed impossible. However I was at the European Lead factory Stakeholder Meeting (24-25 April 2017) and it is clear that is has been a success.

Read More…

Drug Discovery Resources Updates

I've been updating the Drug Discovery Resources section.

In particular I've added a section on target prediction tools, updated the section on Analysis of HTS data, and expanded the section on aggregation in bioassays to include a recent publication giving an example of target specific aggregation.

The crystal structure showing the interaction is available (PDB 5MU8) and is displayed below using 3Dmol.js, the ligand (JNJ525) is shown in red..

Mouse Controls

Movement      Mouse Input      Touch Input
Rotation Primary Mouse Button Single touch
Translation Middle Mouse Button or Ctrl+Primary Triple touch
Zoom Scroll Wheel or Second Mouse Button or Shift+Primary Pinch (double touch)
Slab Ctrl+Second Not Available

In addition I've updated the section on molecular interactions.

European Lead factory Newsletter

The latest issue of the European Lead Factory Newsletter has just been published.

Highlights include the European Lead Factory recently reached the milestone of having received over 1,000 chemical library proposals for consideration. To date, 143,529 novel compounds, out of the 200,000 prospected compounds for the Public Compound Collection, have been synthesized, which means that the ELF compound collection grows daily by approximately 250 novel compounds to eventually constitute the 500,000 Joint European Compound Library (JECL).

Parkinson’s UK and the University of Sheffield have launched a joint venture biotech company, Keapstone Therapeutics. Parkinson’s UK has allocated 1 million GBP over the next sixteen months to further develop compounds that boost the internal cellular defence mechanisms against oxidative stress. These compounds were discovered by European Lead Factory.

The Ecstasy and Agony of Assay Interference Compounds

There is an editorial in ACS Central Science DOI that I would encourage everyone involved in hit identification to read.

A couple of quotes will give you an idea of the content

Alarmingly, up to 80–100% of initial hits from screening can be artefacts if appropriate control experiments are not employed.

it is important to realize that no PAINS-containing drug has ever been developed starting from a protein-reactive PAINS target-based screening hit

They also emphasise the critical need for experimental validation for any screening hit.

Such validation experiments include classic dose response curves, lack of incubation effects, imperviousness to mild reductants, and specificity versus counter-screening targets. If a molecule is flagged as a potential PAINS or aggregator using published patterns but is well-behaved by these criteria, it may be a true, well-behaved ligand. Ultimately, genuine SAR combined with careful mechanistic study provides the most convincing evidence for a specific interaction. Covalent and spectroscopic interference molecules act via specific physical mechanisms, for which controls are known. Colloidal aggregation, fortunately, is readily identified by rapid mechanistic tests and by counter-screening.

In addition you need to consider compound identify and purity, reproducing the activity with an authentic sample is essential.

Whilst time-consuming this validation work will save a fortune in the future.

Peptidyl-Prolyl cis-trans Isomerase (PPIase) assays

Having worked wit Selcia on a number of projects I always keep an eye out for news on their work on Peptidyl-Prolyl cis-trans Isomerases (PPIase). These are very interesting class of enzymes whose principal function is to catalyse the cis-trans isomerisation of the X-Pro peptide bonds in polypeptide chains (where X is any amino acid). This transformation is thought to be a mechanism to modulate protein function.

PPIase

PPIase enzyme targets are of increasing interest in drug discovery due to the extensive potential of small molecule inhibitors in a range of therapeutic areas, including infection, inflammation, cancer and neuroprotection.

Selcia have now expanded the range of Peptidyl-Prolyl cis-trans Isomerase (PPIase) assays they can offer.

The SULSA Assay Development Fund:

I've worked with a couple of academic groups who have a very interesting target but no small molecule leads. Whilst there are several places offering high-throughput screening the stumbling block is often development of a robust screening assay running in a high density format. Most academic groups have little experience in developing such an assay and to be honest will need to do so very infrequently.

The SULSA Assay Development Fund: accelerating translation of new biology from academia to pharma DOI describes efforts to support the development of such assays, work carried out in collaboration with the European Lead Factory in Newhouse.

However, many scientifically interesting, novel molecular targets lack associated high-quality, robust assays suitable for hit finding and development. To bridge this gap, the Scottish Universities Life Sciences Alliance (SULSA) established a fund to develop assays to meet quality criteria such as those of the European Lead Factory. A diverse project portfolio was quickly assembled, and a review of the learnings and successful outcomes showed this fund as a new highly cost-effective model for leveraging significant follow-on resources, training early-career scientists and establishing a culture of translational drug discovery in the academic community.

European Lead Factory technical acceptance criteria

  • Minimally 384 wells (max 30 μl)
  • Homogenous assay (no washing steps)
  • Defined endpoint
  • Z-prime >0.6
  • Readout stability >1 h
  • S/B signal >3
  • Incubation times <4 h
  • DMSO tolerance: minimum 0.5%
  • All reagents minimally 8 h stable
  • Recombinant proteins(s) >80% pure

Perhaps this quote sums things up very nicely.

‘We only got so far in optimising our assay because in my opinion we do not have either the equipment or the personnel with the skill set required to do this efficiently. So being able to come and work at Newhouse where you are then surrounded by people who can identify quickly where assay improvements should be made and then pass on the knowledge of how to set about applying these changes (as well as gaining experience with various pieces of equipment) was invaluable.’

More details are available here http://www.sulsa.ac.uk/sites/sbsweb2.bio.ed.ac.uk.sulsa/files/downloads/SULSAassaydevelopmentfundguidancenotes4.pdf

The Wellcome Trust also provides Seed/Pathfinder awards that could cover similar projects.

Published Fragments Page Updated

I've just updated the published fragments page.

pubfrags

Another European Lead Factory success

We are now starting to see some of the results of the screening of academic projects at the European Lead factory that was initiated in 2013.

Dr Mahlapuu’s group, based at the University of Gothenburg, first identified a new target which could be used to reverse metabolic complications in type 2 diabetes. With the help of the European Lead Factory experts, she then screened the Joint European Compound Library of the then 320,000 industry compounds and identified a set of selective and potent small molecules which interfere with this target.

They have now formed a spinout company to develop these leads. ScandiCure has received 1 MSEK from the 2016 SWElife program to continue the development of first-in-class anti-diabetic drug based on small molecule antagonists of a novel key mediator - serine/threonine protein kinase 25 (STK25).

ELF and antibiotic resistance programme

The latest news report from the European Lead Factory highlights work targeting antimicrobial resistance in collaboration with Professor Chris Schofield (University of Oxford). The high throughput screen of >300,000 compounds and initial triaging provided 50 qualified hits.

Multiple series of compounds were validated through resynthesis, biochemical and biophysical profiling at the European Screening Centre site in Newhouse, complemented with ligand–protein crystallography and antimicrobial evaluation at University of Oxford

Great to see projects like this move forward, demonstrates how important the ELF is in providing hits for academic groups/small companies.

European Lead Factory Update

The latest newsletter from the European Lead Factory has just been published and highlights a number of notable achievements.

As a result of the screening campaigns >3000 qualified hits have been awarded to private and public target owners. 72 public target programmes have been accepted, 48 high throughput screens finished and 41 hit lists with associated data reports handed over to the target owners. >150 bespoke assays have been developed in order to extract the most interesting hits for public programmes.

There are now 450,000 compounds in the compound library of which 120,000 are novel compound specifically synthesised for the ELF.

You can read more details here https://www.europeanleadfactory.eu/results/

The European Lead Factory is a collaborative public-private partnership aiming to deliver innovative drug discovery starting points. Having established the first European Compound Library and the first European Screening Centre, the EU Lead Factory aims to give free access to up to 500,000 novel compounds, a unique industry-standard uHTS platform, and much more.

We are now starting to see publications describing these endeavours..

https://www.europeanleadfactory.eu/results/publications/scientific-articles/

European Lead Factory

The European Lead Factory started work just over 3 years ago and have just released an update on results to date.

The EU Lead Factory is an IMI-funded project that aims to create new chemistry based on crowd-sourced ideas and boost applicants’ drug discovery programmes at no upfront costs

  • A Sweden-based start-up company, ScandiCure AB, has been founded based on the results of an EU Lead Factory target programme. ScandiCure is developed with the support and investment of GU Ventures, which is wholly owned by the Swedish State.
  • Patents on EU Lead Factory compounds for treatment of multi-resistant bacteria infections and cancer.
  • An EU Lead Factory programme accepted by IMI’s ENABLE for preclinical development.
  • In vivo proof-of-concept generated with EU Lead Factory compounds.
  • 2 PhD thesis enhanced with EU Lead Factory target programme assay development and screening results.
  • >35 scientific, peer-reviewed articles, whereof one is the 4th most downloaded article published in Drug Discovery Today in 2015.
  • 450,000 compounds in the Joint European Compound Library (JECL), whereof >120,000 of the prospected 200,000 novel screening compounds have been synthesised. 330,000 compounds were selected and assembled from the EFPIA participants’ proprietary compound collections within 6 months of operation.
  • Many testimonials of the high quality of the EU Lead Factory output and the JECL compounds. For example, 17/49 EFPIA partner screens have triggered further work.
  • 72 public target programmes accepted, 48 high throughput screens finished and 41 hit lists with associated data reports handed over to the target owners.
  • In total, 2925 qualified hits have been granted public and private target owners (1041 and 1884, respectively).
  • >1500 bespoke compounds synthesised in hit validation and hit-to-lead phase of public target programmes.
  • >10 crystal structures of target–compound complexes have been solved.
  • >150 bespoke assays have been developed in order to extract the most interesting hits for public programmes.
  • 12/14 of the public target programmes offered to the industry EFPIA participants have been asked to provide a dossier for further assessment.
  • >30 academic postdoctoral fellows trained in industry methods and approaches.
  • Researchers in 13 countries (BE, DE, DK, ES , FR , IT, IL, HU, NL, PL , PT , SE, UK) involved. Partners spread over 8 countries and target owners over 11.
  • 2 Custom-built data management platforms, the Honest Data Broker system developed to enable screening data management and triaging, whilst ensuring confidentiality and patentability; TarosGate2, a chemistry workflow management system with a secure built-in electronic laboratory notebook.

I’ve been involved in a number of screens and we have been very happy with the results, this is a great resource long may it continue.

It is also worth noting that the next submission deadline is 10th October 2016, here is the link for submitting assays for consideration. https://www.europeanleadfactory.eu/how-to-submit/drug-target-assays/

Fragment based screening

I’ve just updated some of the fragment based screening pages, in particular I’ve updated the section on Published fragment Hits. The database now contains 1216 entries culled from over 240 publications directed at nearly 174 different molecular targets using 26 different detection technologies.

I also noticed that a fragment library I was helped design is now commercially available, The Selcia Fragment Library was designed to have broad applicability and chemical tractability. It is also one of the few libraries where solubility has been confirmed experimentally. The profile of the library is included in the fragment library profiles.


Drug Discovery Resources Updated

I have updated the Drug Discovery section on Screening Collection design.

Drug Discovery Resources Update

I've updated the hit identification section of the Drug Discovery Resources. In particular I've added to the high-throughput screening analysis including more information on PAINS (Pan Assay Interference Compounds) first described by Baell et al DOI and subsequently summarised in an excellent Nature comment.

Academic researchers, drawn into drug discovery without appropriate guidance, are doing muddled science. When biologists identify a protein that contributes to disease, they hunt for chemical compounds that bind to the protein and affect its activity. A typical assay screens many thousands of chemicals. ‘Hits’ become tools for studying the disease, as well as starting points in the hunt for treatments.

These molecules — pan-assay interference compounds, or PAINS — have defined structures, covering several classes of compound. But biologists and inexperienced chemists rarely recognize them. Instead, such compounds are reported as having promising activity against a wide variety of proteins. Time and research money are consequently wasted in attempts to optimize the activity of these compounds. Chemists make multiple analogues of apparent hits hoping to improve the ‘fit’ between protein and compound. Meanwhile, true hits with real potential are neglected.

Also added a page on Aggregators. Promiscuous inhibition caused by small molecule aggregation is a major source of false positive results in high-throughput screening. To mitigate this, use of a nonionic detergent such as Triton X-100 or Tween-80 has been studied, which can disrupt aggregates, and is now common in screening campaigns DOI.

An Aggregation Advisor for Ligand Discovery

Aggregation is a regular concern when evaluating potential hits from screening and a recent paper "An Aggregation Advisor for Ligand Discovery" DOI attempts to provide an insight into this phenomenon, in addition they provide a useful web-based tool http://advisor.bkslab.org that provides a free service to advise whether molecules may aggregate under biological assay conditions.

aggre

European Lead Factory

p>The European Lead Factory has just announced that an additional 50,000 new compounds have been added to their screening collection. This brings the collection up to 350,000 compounds and sets them well on the way to their 500,000 target.

I've been involved in a couple of projects that have made use of this high-throughput screening facility and I've been impressed with the quality and diversity of the hits generated.

The European Lead Factory was established to promote the discovery of novel lead compounds, suitable for subsequent optimization either to drug candidates or to high‐quality pharmacological tools for the experimental validation of targets.

If you have a target you want to screen against you can submit a proposal online. For an academic or small company this is an interesting way to identify novel starting points for a medicinal chemistry program.

Free Compound Screening for antimicrobial activity

The concerns about antibiotic resistance are well known and indeed have made headlines in the mainstream press. Here is a chance to help find the next generation of antibiotics.

Do you have interesting compounds sitting on the shelf? Perhaps you would be interested in having them screened for antibiotic activity for free?

The Community for Open Antimicrobial Drug Discovery would like to hear from you, their goal is to screen compounds from academic research groups from anywhere in the world for free.

The requirements are pretty minimal

We ask for 1-2 mg of pure compound which will be used for primary screening, hit confirmation, and if active will be used for a broader antimicrobial screening, cytotoxicity and a check for its purity. We require all compounds to be soluble in water or DMSO and to be shipped as dry material in appropriate containers, such as 1-2 mL Eppendorf tubes. For larger collections we can arrange plates or tube-racks.

In the primary screen they test against against key ESKAPE pathogens, E. coli, K. pneumoniae, A. baumannii, P. aeruginosa, S. aureus (MRSA), as well as the fungi C. neoformans and C. albicans. The ‘ESKAPE’ pathogens that are responsible for two-thirds of all health care-associated infections and resistant strains of these bacteria represent the greatest unmet need in antibacterial drug development.

New Compound Sets Identified from High Throughput Phenotypic Screening Against Three Kinetoplastid Parasites: An Open Resource

The GSK high-throughput screening group at Tres Cantos and collaborators have just published DOI the results of whole-cell phenotypic screens against the three kinetoplastids most relevant to human disease, i.e. Leishmania donovani, Trypanosoma cruzi and Trypanosoma brucei. Three anti-kinetoplastid chemical boxes of ~200 compounds each were assembled. Functional analyses of these compounds suggest a wide array of potential modes of action against kinetoplastid kinases, proteases and cytochromes as well as potential host-pathogen targets. The compound sets are provided as an open resource for the scientific community.

srep08771-f1

More on PAINS

I often get asked to help with the analysis of high-throughput screening results and one of the first filters I run as part of the hit identification is to flag for PAINS (Pan Assay Interference Compounds) first described by Baell et al DOI and subsequently summarised in an excellent Nature comment.

Academic researchers, drawn into drug discovery without appropriate guidance, are doing muddled science. When biologists identify a protein that contributes to disease, they hunt for chemical compounds that bind to the protein and affect its activity. A typical assay screens many thousands of chemicals. ‘Hits’ become tools for studying the disease, as well as starting points in the hunt for treatments.

These molecules — pan-assay interference compounds, or PAINS — have defined structures, covering several classes of compound. But biologists and inexperienced chemists rarely recognize them. Instead, such compounds are reported as having promising activity against a wide variety of proteins. Time and research money are consequently wasted in attempts to optimize the activity of these compounds. Chemists make multiple analogues of apparent hits hoping to improve the ‘fit’ between protein and compound. Meanwhile, true hits with real potential are neglected.

In the supplementary information they provided the corresponding filters in Sybyl Line Notation (SLN) format, however they have also been converted to SMARTS format and incorporated in sieve file for use in filtering compound collections. If you are a Vortex user then there is also a Vortex script available, filters are also available for Knime and now it is even available on mobile devices with MolPrime+.

It is probably not until you have been involved in multiple small molecule screens that you appreciate the number of ways that false positives can occur and just how much valuable time and resources can be wasted following them up. Indeed it may be for the more difficult targets the majority of hits seen may be false positives. Flagging PAINS is now such a well developed tool that it would be fool hardy not to include it.

Drug Discovery Resources Updates

I’ve made a couple of updates to the Drug Discovery Resources pages. In particular I’ve updated the Published fragments Hits to include more examples, details of “promiscuous” compounds and summary of detection technologies and the targets explored. I’ve also updated the Aspartic Protease inhibitors page.

As ever comments and/or suggestions very welcome.

Kinase Inhibitors

I’ve updated the Drug Discovery Resources to include a page on Kinase Inhibitors. I will be expanding it over the next week, so any comments or suggestions welcome.