Science@home for everyone – the quick and simple(st) way

Do you want to do contribute to research but don’t have the time/nerve/know-how for any kind of deeper involvement? Of course you want to ๐Ÿ˜€ !
And yes, it is possible! The answer is – distributed or volunteer computing!

This is not a new phenomena, it has been around for quite a long time now. One of the more know projects most likely is SETI@home, where you help analyze radio signals from space in the search for extra-terrestrial life.
Today, the field of distributed computing encompasses all kinds of research areas, including drug discovery. One of many summaries on this subject can be found on this blog by the OpenScientist and of course Wikipedia, on Volunteer Computing.

Thus, by allowing your computer to calculate on behalf of whatever research in question, you indirectly contribute to that project – without lifting a finger. The only thing you need to do is install a program, register yourself as user (for some you can even just run anonymously) with a tiny caveat that you also “contribute” with electricity. But hey – it’s for science, right? In addition, some projects include a fancy looking screen saver!
Don’t want to have your computer on all the time? Don’t want to be bothered while you are using your own machine? No problem, nearly all allow AFAIK several ways to restrict the client with regards to CPU/GPU usage or the time it may run or not.

Can’t decide what to contribute to? Want to contribute to multiple projects but not have multiple clients installed/have to keep track off? Then I can recommend the World Community Grid which supports out-of-the-box 7 different projects. And if I am not mistaken, with a wee bit of manual work, you can make the client run other projects via this client. And if you prefer doing something like this while playing a video-game, even that is possible, for example in EVE Online or FoldIt (these though require a bit more “work” requiring active inputs/analysis by the user and thus go beyond the idea of “simplistic” distributed computing).

Myself, I am supporting the OpenZika project, due to some personal interest in this field. Come join me and many, many others!

Click here to get started!
(Note: this includes my referral ID – don’t worry, there is no money involved, it simply gives out “badges” for “recruitment”. Use the above World Community Grid link instead if you don’t like this idea).

Docking & virtual screening @home – preview

Way too many things have been happening lately, I didn’t have the time as I’d like to write new entries, one of them is the start of a new Job within the next few days ๐Ÿ˜€ [That’s a valid excuse, isn’t it?]

Anyway, a bit more complex and especially CPU/GPU heavy task is docking and receptor modelling. It depends though on what you think you want to do –

Do you just want to dock the occasional molecule(s), maybe make a nice picture, then you should be fine with a low-spec configuration as described in my post Part 1 of Drug Research @home . If you intend to do high throughput virtual screening of tens or even hundreds of thousands of compounds, you either have to have a lot of patience (in the range of days to weeks) or a lot of money for a cluster [I am not going into the possibility of using cloud-services (yet), though that would probably be an option as well].

The system I will describe is AutoDock, resp. Vina, the simplest and most “open-sourced” docking software, and combine it with other free tools for visualization, respectively preparation.

As time/computational reference: Docking a single molecule with Vina on an average modern i7 system takes ca 20-30 seconds. That’s ok for several hundreds at once. While I previously had access to Xeon based Linux Cluster, I screened 80k compounds on 12 CPUs in 10 or so days…. (well, it was a queue system shared with other users, though the way the system was set up it was more or less constantly calculation,).

Now, using Vina isn’t new and there are descriptions out there, but few deal (if at all) with automation. Furthermore, you have to pick bits and pieces from different places and combine them, which isn’t as obvious as one might think if you aren’t an expert (well, at least I don’t consider myself one in this particular field).

Until soon!

 

Abuse of open access tools and data?

As in a previous blog of mine described, it is rather simple to set up virtual compound design from the comfort of your home. Tools and data are easily accessible and hardware is cheap. Add to that a bit more hardware, maybe even a (garage) laboratory – it makes you wonder “What If”?

Is it possible that open access data is abused for criminal purposes, in particular recreational drugs? I recon it it would make sense (unfortunately) and I am sure there are more articles to be found other than the one I stumbled upon recently, dating back to 2013, by the Guardian. Though they don’t give any source or example for their (probably legitimate, imho) claim of what/were “clandestine” labs are.

Synthesis of known (recreational) drugs have been accessible since the days of Usenet newsgroups (seen them myself back in the days) and probably even BBSs. And then there is of course PhiKal, perhaps one of the main sources for Usenet/BBS in those days, before internet became bigger and easier accessible. With that know-how also follows a list of how to replace certain ingredients with household items/chemicals as replacement of otherwise only laboratory accessible items. It is so simple nowadays, a simple Google search will yield e.g. the recipe for crystal meth based on household chemicals; “Breaking Bad” in real life.

Combine the urge do to something like this with knowledge on pharmaceutical design and open accessโ€ฆ..

Though as long as as so called designer drugs seem to be based on arbitrary testing of only slightly modified existing compounds – one of many examples fitting that picture seems to be acrylfentanyl – it doesn’t look like  open access is the culprit (yet).  It’s more the usual greed and stupidity with as fast, simple and cheap turn-over as possible – health and safety concerns have never been on the agenda. The only optimization probably is accessibility of starting materials. If there is anything valid to the above mentioned article, then of course the synthesis can go beyond your local garage and is done by “professionals” with expert equipment and chemicals. But hey, maybe I am naive and there are pro-labs doing all the typical design and test cycles as a pharmaceutical company would do…. Not that that is a good justification for illegal drugs.

It’s a rather scary thought – I am not sure what, if anything at all, can be done about this.

Perhaps the law-makers should start banning substances based on their pharmaceutical action, or generic structure (Markush like?), rather than one-by-one. I believe a similar problem exists in the area of sports & doping, were new “undetectable compounds” turn up faster than anyone has time to analyze and make new laws prohibiting previously identified ones.

I (obviously) can only recommend against any type of creating existing or new drugs – not only from a substance abuse of legal issue, but also from a plain health perspective – putting untested “shit” into your body will lead to – shitty results, plain and simple.  And if you are not a chemist doing “shit” in your garage, well, count on “shit” happening.

Drug research at home – (how) is that possible? – Part 2

Continuing on after part 1:

What to do with the tools

I’m assuming that you have (some) knowledge on how to search, what to look out for, a  workflow on the different steps required to do the job. It’s otherwise a topic on it’s own for another time. Not that it hasn’t been described before, alas, no, see just one example here:

Nicola, G., Berthold, M. R., Hedrick, M. P., & Gilson, M. K. (2015). Connecting proteins with drug-like compounds: Open source drug discovery workflows with BindingDB and KNIME. Database: The Journal of Biological Databases and Curation, 2015, bav087. https://doi.org/10.1093/database/bav087

Actual Compounds

So you identified something and want to test your hypothesis beyond in-silico. Well, that is a bit tougher – you can’t really handle and test compounds at home. Theoretically though,  you could have someone else do this part for you (order commercial compounds, synthesize something new, test in a biological assay). That is (unfortunately) not for free.

Though to obtain compounds ,if you are (or have connections to) academia or a (smaller) company, there are some interesting initiatives are available, such as within Malaria research by http://www.mmv.org/research-development/open-source-research/open-access-malaria-box, though now more broadly for pathogens at http://www.pathogenbox.org/. Then there are possibilities as described in the next section.

Once you think you have something

Actual testing aside (it never hurts), what can you do with those cool results? Well, there are a number of things – the simplest one would be: write a blog! More involved and scientifically more appropriate – at the same time more difficult – write a publication in a scientific journal or present at a scientific meeting. You could even try and patent your findings, if you have the finances. It all depends on the impact you want to have.

To go beyond a publication, if you want to be part of/follow your findings, you can contact some of the initiatives by pharmaceutical companies who are open to collaboration on new findings. For example,  Johnsson&Johnsson [jnjinnovation.com/partner-with-us], or AstraZeneca [openinnovation.astrazeneca.com], or the Medicines for Malaria Venture [www.mmv.org/partnering/our-partner-network] and many more. You can also find incubators within academia, but then you would require some contact to a research group within. The list of incubators/companies & universities is nowadays quite big and could be a topic for a separate blog entry.

If you are really in it for the money though, I think you will be disappointed. Doing drug research from home is more like a hobby just fun, in the best case though for the greater good. Having said that, should you really find something interesting and you contact any of the above mentioned initiatives, intellectual property and reimbursements will most likely be on the table at some point.

Now, start researching!

Drug research at home – (how) is that possible? – Part 1

In the current day and age of open access information, combined with cheap computing power, it is rather simple to do (some) drug research from the comfort of your home, be it as private person for fun or out of interest, or as a small (start-up) company. Actually, big pharma companies use some of the same resources combined with their own in-house data and programs as well – so why shouldn’t you?  

Where is this data? What kind of data?

There are a number of public- so called open access – databases available these days, curated over many years by high profile institutes, as e.g. the National Institute of Health, NIH for Pubchem.  Many more institutions and specific initiatives have evolved over many years, some appearing literally right now, depending on the field and data. Databases on chemical compounds, small molecules, have been around the longest, afik, with structure, properties, literature references and biological data associated.

Listing all of them would require an entire Wikipedia page (or more), and that work has already been done – you can find a substantial list here for example http://oad.simmons.edu/oadwiki/Data_repositories, though in terms of life science, on this NIH site, you can really knock yourself out: https://www.ncbi.nlm.nih.gov/guide/all/#databases_. The scientific literature has regularly some article on databases and software, as well as many blogs do, but that is outside of this scope.

More focused for our purpose of drug research, you have sites such as PubChem, BindingDBZinc, or e.g. GuideToPharmacology. I’d say with these you can get pretty far.  Curated from literature and also patents, these databases connect structures to biology, i.e. mechanism of action, structure of the target, how much is know about it (or not).  All sites and db-s are arranged differently, some you can search on the web, via an API, some by browsing, or a combination thereof. Then, there are also the semi-public databases, such as CDD-Vault – you can register and search within the public databases (all via the web, independent of your machine power), though you cannot download or batch process on the free account. It might still be worth a look at times considering you find data which is not in literature/patent based curated databases.

What will you need?

A certain understanding of the drug discovery process, chemistry and some degree of biology. If not yourself, then a good friend who might have that knowledge and can support you (though this seems like a unlikely scenario?). Some IT-skills certainly don’t hurt. Below I will focus on data-mining as the core task of the home research, methods such as docking or quantum mechanic calculations I will leave out for now.

Hardware
  • A(ny) computer – Windows, Linux, Mac – doesn’t matter.
    In my experience though when it comes to chemistry, the Windows platform still offers a broader range of both commercial and freeware programs .
  • How powerful?
    Simply put, also doesn’t matter. Sure, the more power, the smoother your experience, though for mining purpose I would go for more memory before processing power. An Intel i3 with (minimum) 16GB of RAM can get you pretty far with little money. Only for large data sets and more complicated calculations I feel this being a bit of a bottleneck. If you have an i7 or Xeon available, good for you!
    What about graphic cards? That actually doesn’t matter for data-mining and simple visualizations. Once you want to do some visual 3d-docking though, that’s another story.
  • An alternative, or even complimentary solution is a (powerful) workstation, placed “anywhere”, which could e.g. be shared with someone else sharing investment costs and then access it via any (simple) PC/Laptop via remote access, e.g. TeamViewer. Cloud computing@home so to say.
  • Reasonably fast internet connection  – for mining those web-services.
Software
  • Knime (available on all platforms) allowing for flexible, visual and fast development of search and analysis workflows.  Combined with some know-how on Java or XML and you have quite a powerful package. To start your journey, you can use some of the readily available (example) workflows before getting into details.
  • A chemical drawing program – there are a rather larger number out there, it is difficult to really make a good suggestion. Knime itself comes with a “myriad” of plugins for structural input and output, thus you actually don’t really need a separate program. Myself, I do have the free Marvin package by Chemaxon installed.
  • DataWarrior – a great package for visually guided “manual” mining, sort of “Spotfire light”, if you will.
  • Excel – or similar, can be used as light weight DataWarrior alternative, but also useful for sharing or storage (as would be Word or Powerpoint (and alternatives).
  • Scripting languages – R or Python – are not necessary, though they can make a good complement, depending on your requirements.
  • Java – also not necessary, but since Knime is built on Java, it sometimes can help for certain work-arounds.
  • XML, HTML, REST – some basics might be helpful when accessing certain services via network API.

What if you don’t know Java and such? Don’t fret, initially, I for example didn’t either. If you are though a person who is more of a “learning by doing”, then the knowledge will come automatically. Obviously, you can learn these in courses as well.

Continued in part 2.