New release! Live-docking, property filtering, new table view

After the first release of mcule, which included basic searching functionalities, we have been working hard on the integration of several new features. I'm pleased to introduce:

Docking (Vina)

Yes! Docking is part of the release pack, and we believe that this will really make a difference! There are a few docking servers available on the net, but have you ever heard about live-docking? Check this out:

After you launched the docking you can start browsing the results as soon as the first few calculations are finished.

One other cool functionality is that you can select your target from among ~10k PDB structures prepared for docking. Many thanks for the group of Prof. Didier Rognan for allowing the integration of sc-PDB [Meslamani J, Rognan D, Kellenberger E. sc-PDB: a database for identifying variations and multiplicity of 'druggable' binding sites in proteins. Bioinformatics. 2011 May 1;27(9):1324-6.] with mcule. This is a great benefit for our users as you can now directly select targets by searching for PDB ID, Protein name, Organism name, UniProt Name/Accession ID/Taxonomic ID. The centre of the binding site will be also automatically determined based on the position of the co-crystallized ligand. All these protein structures have been automatically prepared for docking. Besides selecting your macromolecule from the sc-PDB database, you can upload your own structures as well.

For docking, we use the latest version of the open-source docking tool AutoDock Vina [Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem. 2010 Jan 30;31(2):455-61.]. We were quite satisfied with Vina in the past, as it was involved in our GPCR fragment library design protocol, which yielded 100% hit rate. 

Property

There is a property filter, where you can set minimum and maximum boundaries. Available properties are either calculated from the InChI string (molar mass, number of atoms, heavy atoms, hydrogens, heteroatoms, stereocentres, cis-trans double bonds), or by OpenBabel (logP, PSA, molar refractivity, number of rings, rotatable bonds, H-bond donors, H-bond acceptors) [O'Boyle NM, Banck M, James CA, Morley C, Vandermeersch T, Hutchison GR. Open Babel: An open chemical toolbox. J Cheminform. 2011 Oct 7;3:33.]. Besides these, rule-of-five and rule-of-three violations are also calculated.

Table View

We have designed a new view, which makes browsing the results even more efficient.

In the new table view you can set which properties (including screening results, e.g. docking scores) you would like to display. Now, you might have seen molecule databases displayed in a useful and transparent way on the web before (there are not many good examples though), but I doubt you have ever been able to sort that database as blindingly fast as you can from now at mcule.com. Believe it or not, sorting of many hundreds of thousands or even millions of molecules can be done in a few seconds(!). Remember that you are using a website and not a desktop application.

Sampler

There is another filter, called Sampler. It can be used to cut the database at a certain threshold and retain only the top x number of molecules. By default it retains the top molecules highest ranked by the previous filter, but it can be set to sample the molecule collection randomly.

It is also important to mention that more advanced features are provided for free with some limitations. The maximum number of molecules for docking is currently set to 500 per month. Sampler is an efficient way to reduce the number of input molecules for such limited filters. We will provide subscriptions with much less boundaries on the website soon. Until then, contact us if you need more!

OK. So now you can go and do some docking if you like, but remember that many other features are underway, so there is more to come! Keep looking at this blog for more!

Mcule presentations and exhibition at ChemAxon UGM

We are attending the ChemAxon User Group Meeting held in Budapest (Hotel Novotel) between 21-23 May 2012. We will deliver a talk about mcule in the Partner Session (01:45pm-03:15pm, 22nd of May), and will be exhibiting, so meet us during the coffee breaks in the exhibition area!

Why are we attending? If you have already attended any of the ChemAxon UGMs, you will know that this is a very exciting event with special social programs. This is probably enough for a reason as itself, but even more importantly, we have started the integration of ChemAxon tools into mcule! This means that soon you will be able to subscribe for ChemAxon packages at mcule.com.

So, come and meet us if you will be around!

Video presentations of ACS, San Diego are now online

If you have missed our presentations from the 243rd ACS Nation Meeting in San Diego, you can watch them online here:

1. Mcule.com: A public web service for drug discovery
2. Registration system of mcule: InChI is the key

You can check about 400 other presentations online here.

Metformin for treating blindness

I found this nice example for polypharmacology on Science Blog about a new indication of metformin.

Here is metformin:


The story in a nutshell:

"University of Texas Medical Branch at Galveston researchers have discovered that ... metformin, which is commonly used to control blood sugar levels in type 2 diabetes, also substantially reduced the effects of uveitis, an inflammation of the tissues just below the outer surface of the eyeball. Uveitis causes 10 to 15 percent of all cases of blindness in the United States. The only treatment now available for the disorder is steroid therapy, which has serious side effects and cannot be used long-term."

I found an ancient article suggesting that metformin acts as a weak histamine agonist, but only histamine H1 and H2 receptors were available at that time. This paper shows that metformin can increase gastric acid levels which is probably associated with a weak H2 stimulation. It would be interesting to see if metformin has got a significant level of H4 affinity. Since H4 antagonism has been shown to reduce inflammation, H4 affinity of metformin might be the missing link here.

In fact, we and others have already found several guanidine containing H4 ligands, see some examples here:

This compound was found by our large-scale structure-based H4 screen.

This is agmatine, published as a low affinity H4 ligand in this paper.

This is VUF8430, another H4 ligand published in this paper.



Anyone interested in measuring the H4 affinity of metformin? :)

Software for all at mcule.com

In the previous blog post, I commented on some aspects on the “Federation of Independent Researchers” – an interesting initiative for smaller players of the pharma/biotech industry. Among the comments on the original post in Derek Lowe’s In the Pipeline, there were a few about software needs of individuals and small companies. For example:

"I'm intrigued by the idea relating to computational chemistry software and finding a way for small companies, particularly startups, to get access to sophisticated modeling and docking software."

Sophisticated modelling tools are expensive. No question. In fact, industrial, annual subscriptions range from $5-200k. Open source is free. So it is quite logical to suggest putting together a software package from open source modelling components. As the comment follows:

"… all the underlying force fields and QM models have been published … it would just take a team of dedicated programmers and computational chemists time and passion to create it"

There are several passionate open-source chemoinformaticions with great expertise, so this part is OK. But time is always an issue as pointed out by Rajarshi Guha:

"It just needs somebody with the time and expertise to implement them. And the combination of these two (in the absence of funding) is not always easy to find."

The other problem is that open source tools are generally not developed systematically enough to provide a complete solution. The development is typically governed by the contributors’ (academic) projects and open-source codes are generated on the side for problems the contributors have to solve anyway. Because of that there always will be missing components. So it looks that providing a complete solution would need several passionate developers working on this full-time, systematically. Putting together the pieces, adding some glue where needed and writing the missing components to complete the jigsaw puzzle. And this is what mcule.com is doing: we integrate. This is a large jigsaw puzzle though. In the absence of funding, this needs a business model. Many people have asked what’s the business model behind mcule.com? So here are some thoughts:

The puzzle wouldn’t be complete without the commercial tools that have been developed for years and reached a level that makes them superior for several tasks compared to open-source ones. We negotiate good prices with software developers and provide them at mcule.com on a subscription basis.

1. First main difference from standard commercial tool licenses is that we provide subscriptions for 1, 3, 6 and 12 months. This will allow people to subscribe for a tool for a single project only and don’t need to pay for an annual license. We think that this will attract smaller companies and individual consultants, who can’t afford maintaining long-term licenses, but want to get tools for single projects. This will be possible at mcule.com.
2. We provide full IT infrastructure: you do the clicks at mcule.com, we run the calculations automatically on the cloud. No hardware investments, no maintenance costs, no need paying for system administrator, etc.
3. Licenses are not CPU limited. What we limit is the maximum number of molecules that these tools can be applied to. This is much more calculable than the number of CPUs. Let’s imagine someone wants do make a large-scale docking. I’m not sure he/she will be able to calculate how long the calculations will run on X number of CPUs. But he/she will definitely know better how many molecules will be screened.

One commenter on the thread said:

"I'm thinking of some kind of virtual server, or remote desktop style operation. Your individual contractor can connect from wherever, and have full access to a range of tools, then transfer their data back to their own location for safekeeping. You would need some kind of central server farm somewhere, but this could probably be hosted on one of the increasing number of cloud services floating around the net these days."

Looks like we can read thoughts. This is exactly what we do.

This is a whole new business model though, not just for us, but most importantly for software vendors. So then comes the question from one of the commenters on Derek Lowe’s blog post:

“Can we propose an alternative business model to software vendors?”

Honestly, we weren’t sure about that at the beginning. But now we can say: Yes, we can! We are very close to sign agreements with some of the big players on the modelling software market. Why is this interesting for them? For various reasons. Most importantly, they were unable to collect long tail users so far. Big pharma has a large budget, can make long-term decisions, has the IT infrastructure in-house, people for maintenance, etc. What’s available from these on the other side? None. So what will a start-up biotech say to an offer for a single tool license alone for $20k? No, thanks. So, how about this other offer for the same tool for a single project (1 month license), complete IT infrastructure, unlimited CPU, no maintenance, no installation, ready to use for $5k? I think that’s something that can work, but we will see what our users will say. I think it is competitive with maintaining significant IT resources, spending days with finding free tools, installing them, writing the missing components, etc. and it is definitely competitive with buying an annual license alone for $20k.

I really liked the renting idea of DeepDyve by making scientific papers available for a few days - an alternative of annual journal subscriptions. I think mcule provides something similar by offering 1 month subscriptions for software. Plus we offer a lot more. Here are the plans:

1. Open community

Since we use some resources developed by the open-source community, we try to give back something. So, people can use open-source tools with some limitations free-of-charge at mcule.com taking that the resulting molecule collections will be public too. This might be an option for people working on non-profit projects e.g. on neglected diseases.

2. Academic users

Significantly reduced prices compared to industrial ones. Resulting collections can be private.

3. Small companies, consultants

Short-term licenses and different bundles/packages can be attractive for small industrial users. We also remove significant burden from their shoulders by providing the IT infrastructure and everything as ready-to-use.

4. Big pharma

Long-term licenses are also available. We provide enterprise solutions to adjust this plan to the actual needs of the companies. They might be interested in the following components: large range of tools, validated screening workflows, large purchasable compound library and easy, single package compound ordering.

What do you think about the above plans? Would be any of these plans interesting for you? I would be very interested to hear opinions!

Besides software, all the users get access to a high quality, up-to-date molecule database, which is the other main component of mcule.com. I will write about this in more detail in the next post!

ACS vs. SCA

I read an interesting blog post at Derek Lowe’s In ThePipeline about a proposal for a “Federation of Independent Scientists”.

Some background: drug discovery and thus the pharma industry are in big trouble (we all know about the increasing costs and small number of approved drugs). Taking the extremely large economical contribution of the pharma industry the consequences are very serious. Unfortunately, drug discovery projects typically span 10-15 years and therefore even if we change something at the front, we won’t see the difference for a while at the end. Nevertheless, everybody agrees that something should be done differently. Different companies give different answers to the problem. Some of them, like AstraZeneca and Pfizer, chose to shut down several sites to cut back costs, thus increasing the number of unemployed scientists and this is the point where this gets a social problem. Since the chances to find a place at another big pharma is relatively low these days, and the number of available academic positions is limited, some of these people join to small biotechs, or found a company themselves or become consultants. While these plans have several advantages, being alone or playing in a small team always limits the resources for getting the job done. Thus the proposal of Mrs. McGreevy:

“What about a voluntary association of independent research scientists?”

Proposed names for this association were: "Federation of Independent Scientist" or "SCA - Society for Chemistry in America" (opposite of ACS).

Members of the association could basically get:

1. Group rates on health and life insurance
2. Group rates on access to journals and library services
3. Online community for support and networking
4. Support for grant writing
5. Marketplace (advertising and bidding for contracts)
6. Special rates for other resources like HTS libraries

I think using the group power to negotiate with suppliers on the above products/services is definitely a good idea. On the other hand, it looks to me that ACS has already addressed most of these points, at least they are offering group rates for insurances, ACS publications, plus free networking, and career opportunities. To make it clear, I’m not saying these problems have been solved already. In fact, there are a lot of non-ACS journals and access to the ACS publications is still too expensive especially for unemployed people. All I’m saying is that before starting a new association, why not trying to urge ACS to make further steps? Building up a new association is hard work, and unemployed people don’t have years to wait for this to be evolved. ACS probably has enough power to negotiate with suppliers of any kind, and probably can provide better discounts of his own publications if it is forced. The question is: do the supporters of the idea have enough power to persuade ACS to make such changes? ACS currently has about 160,000 members. I think if this initiative can gather ~10,000 supporter members, then it can make a difference. I'm maybe a little naive, but if the number of demanders will be large enough, I don’t think ACS could ignore them. 

Besides this, several of the commenters mentioned already available solutions for some of the listed problems. In particular, DeepDyve can be an alternative for annual journal subscriptions. DeepDyve provides a renting service of scientific papers for $0.99. Renting means: viewing is allowed, downloading is not. While the list of accessible journals is impressive, I don’t see any ACS journals. Again it might sound naive, but why not urge ACS and DeepDyve to start negotiating and make an even more attractive renting service model for ACS members?

Some of the commenters brought up another major problem, namely the need of modelling software. Most of the small biotech companies and also consultants need some tools to work with, but prices of commercial software are high and it is not the only expense here: hardware infrastructure, maintenance, data and software integration, etc. Looks like mcule.com was a good idea! I will write about our solution for these problems in an upcoming post. Stay tuned!