From owner-chemistry@ccl.net Mon Dec 13 09:18:00 2010 From: "miriam sgobba miriam.sgobba||gmail.com" To: CCL Subject: CCL: Prediction & Identification of protein-ligand binding sites Message-Id: <-43366-101213053439-31866-j8vfNZdFNQKVuSPJuCmdEw-*-server.ccl.net> X-Original-From: miriam sgobba Content-Type: multipart/alternative; boundary=001636c5b27dae8a2a0497483f9a Date: Mon, 13 Dec 2010 10:34:28 +0000 MIME-Version: 1.0 Sent to CCL by: miriam sgobba [miriam.sgobba . gmail.com] --001636c5b27dae8a2a0497483f9a Content-Type: text/plain; charset=ISO-8859-1 Content-Transfer-Encoding: quoted-printable Dear Deepangi, if you know from experimental data one or more compounds that bind your protein, you can also try the blind docking technique, which allow you to perform docking simulations on large surfaces of the protein in order to ge= t unbiased mapping of the ligand. For references, see: http://www.sciencedirect.com/science?_ob=3DArticleURL&_udi=3DB6T36-4J5D6GW-= 5&_user=3D126523&_coverDate=3D02%2F20%2F2006&_rdoc=3D1&_fmt=3Dhigh&_orig=3D= search&_origin=3Dsearch&_sort=3Dd&_docanchor=3D&view=3Dc&_acct=3DC000010358= &_version=3D1&_urlVersion=3D0&_userid=3D126523&md5=3D9fb1be8e42cf768ac87b92= 1ab39d056b&searchtype=3Da http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2373668/?tool=3Dpubmed and, for some blind docking applications: http://www.springerlink.com/content/p237tl40785m1tu5/ http://pubs.acs.org/doi/abs/10.1021/ci1001857 Usually, a blind docking simulation is followed by a focused docking and post-docking refinement if you want to better characterize the ligand binding mode. In my experience, a consensus among binding site identification methods (both geometrical and energetical) + blind docking technique is the best choice to identify a ligand binding site. Hope this helps! Good luck! Miriam 2010/12/12 Deepangi Pandit deepangi.pandit++gmail.com < > owner-chemistry _ ccl.net> > > >> Sent to CCL by: Deepangi Pandit [deepangi.pandit|,|gmail.com] >> Thank you Peter, for your detailed reply. I would just like to clarify >> my case based on your questions. >> >> > 1 : Do you want to apply this method on a database of proteins or just= a >> few structures? >> >> I am looking at just a few structures to identify the putative drug >> binding site. I have PDB files of protein structures (of course, >> without the compound) and have experimental data which suggests the >> compound is binding but do not know where. >> >> > 2 : Do you want to identify putative drug binding sites or whatever >> binding site a method could find (general purpose pocket prediction) >> >> I am trying to identify the putative drug binding sites not general >> purpose pocket prediction >> >> >> > 3 : Do you want to find conserved pockets among homologs? >> >> This is not my primary goal. >> >> Best, >> Deepa >> >> On Sat, Dec 11, 2010 at 4:45 PM, Peter Schmidtke >> pschmidtke[-]mmb.pcb.ub.es wrote: >> > >> > Sent to CCL by: Peter Schmidtke [pschmidtke[*]mmb.pcb.ub.es] >> > Dear Deepangi, >> > >> > protein-ligand binding site detection is a very active field and there >> > is a large variety of methods out there. >> > Since the publication of PocketPicker >> > (http://www.journal.chemistrycentral.com/content/1/1/7/abstract/) lots >> > of newer methods used the comparative table that was published with >> > PocketPicker (table 2). A very recent example is the paper by Andrea >> > Volkamer, where you have an update of this table with a few more recen= t >> > methods (http://pubs.acs.org/doi/full/10.1021/ci100241y). >> > >> > This comparison is definitely arguable, but at least it gives some hin= t >> > on general pocket prediction performance. In order to find the perfect >> > method for your purpose you should maybe clarify what is the >> > functionality your are seeking. There are lots of webservers out there= , >> > methods you have to pay and also free methods. >> > >> > Some questions that could influence your choice : >> > >> > 1 : Do you want to apply this method on a database of proteins or just= a >> > few structures? >> > 2 : Do you want to identify putative drug binding sites or whatever >> > binding site a method could find (general purpose pocket prediction) >> > 3 : Do you want to find conserved pockets among homologs? >> > >> > Concerning question 1, if you just need a method for a few structures >> > you can go for slower programs (mostly energy based algorithms) like >> > SiteMap from Schr=F6dinger (but you need a license) Q-SiteFinder or >> > PocketPicker or Vice (I think it's sold by Tripos) There are surely mo= re >> > than that. >> > If you need to process a large number of structures, considering >> > geometry based methods might become an interesting choice. Choices cou= ld >> > be Ligsite, fpocket, PASS, SiteFinder (included in MOE by CCG) ... >> > >> > Regarding question 2. Pocket prediction is not equal drug binding site >> > prediction. Recent druggability prediction methods have been published >> > and some scores are available ready for use in SiteMap (I don't know i= f >> > you still have to calculate it or if they finally included it into the >> > SiteMap distribution) and fpocket. I suspect also QSiteFinder might gi= ve >> > indications on druggability (I extrapolate from the methodology I just >> > read very quickly, so maybe I'm wrong here ;) ). >> > >> > Regarding question 3, I think ligsite csc can help there >> > (http://projects.biotec.tu-dresden.de/pocket/), or else hpocket, which >> > is part of the fpocket webserver : >> > http://bioserv.rpbs.univ-paris-diderot.fr/fpocket/ >> > >> > I hope that this gives you at least a direction, there are really lots >> > of methods and it is indeed not easy to know which one to use ;) >> > >> > Ah, I nearly forgot, metapocket2.0 is a sort of consensus pocket >> > prediction method that makes use of LIGSITEcsc, PASS, Q-SiteFinder, >> > SURFNET, Fpocket, GHECOM and ConCavity. This has again advantages and >> > disadvantages, but well, at least you know that it exists ;) >> > >> > Good luck. >> > >> > Peter Schmidtke >> > >> > >> > >> > >> > On 12/11/2010 06:44 PM, Deepangi Pandit deepangi.pandit~!~gmail.comwro= te: >> >> Sent to CCL by: Deepangi Pandit [deepangi.pandit(!)gmail.com] >> >> Dear All: >> >> I tried to search literature and Internet to find a reliable method >> >> that I can use to identify protein-ligand binding site. I came across >> >> number of papers but I am unable to evaluate the methods before I >> >> start using them. I was also unable to find a review which compares >> >> the methods. It seems method can be broadly classified as "Geometry >> >> based" and "Energy Based". Could you please recommend from your own >> >> experience which method gives reasonable results. Also, feel free to >> >> share pros and cons of the method. >> >> >> >> Thank you. >> >> Deepa >> >> >> >> List of methods I came across >> >> >> >> Q-Site Finder >> >> http://www.bioinformatics.leeds.ac.uk/qsitefinder >> >> >> >> Surface triplet propensities >> >> http://opus.bch.ed.ac.uk/stp >> >> >> >> Screen >> >> http://interface.bioc.columbia.edu/screen> >> > >> > >> >> >> >> -=3D This is automatically added to each message by the mailing script = =3D->> >> >> > --001636c5b27dae8a2a0497483f9a Content-Type: text/html; charset=ISO-8859-1 Content-Transfer-Encoding: quoted-printable Dear Deepangi,

if you know from experimental data one or more=20 compounds that bind your protein, you can also try the blind docking=20 technique, which allow you to perform docking simulations on large=20 surfaces of the protein in order to get unbiased mapping of the ligand. For references, see:
http:= //www.sciencedirect.com/science?_ob=3DArticleURL&_udi=3DB6T36-4J5D6GW-5= &_user=3D126523&_coverDate=3D02%2F20%2F2006&_rdoc=3D1&_fmt= =3Dhigh&_orig=3Dsearch&_origin=3Dsearch&_sort=3Dd&_docancho= r=3D&view=3Dc&_acct=3DC000010358&_version=3D1&_urlVersion= =3D0&_userid=3D126523&md5=3D9fb1be8e42cf768ac87b921ab39d056b&se= archtype=3Da

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC23736= 68/?tool=3Dpubmed

and, for some blind docking applications:
<= br> http://www.springerlink.com/content/p237tl40785m1tu5/
http://pubs.acs.org/doi/abs/10.1021/ci1001857

Usually, a blind docking simulation is followed by a focused docking and=20 post-docking refinement if you want to better characterize
the ligand binding mode.
In my experience, a consensus among binding=20 site identification methods (both geometrical and energetical) + blind=20 docking technique is the best choice to identify a ligand binding=20 site.

Hope this helps!
Good luck!

Miriam


2010/12/12 Deepangi Pandit deepangi.pandit++gmail.com = <owner-chem= istry _ ccl.net>


Sent to CCL by: Deepangi Pandit [deepangi.pandit|,|gmail.com]
Thank you Peter, for your detailed reply. I would just like to clarify
my case based on your questions.

> 1 : Do you want to apply this method on a database of proteins or just= a few structures?

I am looking at just a few structures to identify the putative drug
binding site. I have PDB files of protein structures (of course,
without the compound) and have experimental data which suggests the
compound is binding but do not know where.

> 2 : Do you want to identify putative drug binding sites or whatever bi= nding site a method could find (general purpose pocket prediction)

I am trying to identify the putative drug binding sites not general
purpose pocket prediction


> 3 : Do you want to find conserved pockets among homologs?

This is not my primary goal.

Best,
Deepa

On Sat, Dec 11, 2010 at 4:45 PM, Peter Schmidtke
pschmidtke[-]mmb.pcb.ub.= es <owner-chemistry|-|c= cl.net> wrote:
>
> Sent to CCL by: Peter Schmidtke [pschmidtke[*]mmb.pcb.ub.es]
> Dear Deepangi,
>
> protein-ligand binding site detection is a very active field and there=
> is a large variety of methods out there.
> Since the publication of PocketPicker
> (http://www.journal.chemistrycentral.com/content/1/= 1/7/abstract/) lots
> of newer methods used the comparative table that was published with > PocketPicker (table 2). A very recent example is the paper by Andrea > Volkamer, where you have an update of this table with a few more recen= t
> methods (http://pubs.acs.org/doi/full/10.1021/ci100241y).
>
> This comparison is definitely arguable, but at least it gives some hin= t
> on general pocket prediction performance. In order to find the perfect=
> method for your purpose you should maybe clarify what is the
> functionality your are seeking. There are lots of webservers out there= ,
> methods you have to pay and also free methods.
>
> Some questions that could influence your choice :
>
> 1 : Do you want to apply this method on a database of proteins or just= a
> few structures?
> 2 : Do you want to identify putative drug binding sites or whatever > binding site a method could find (general purpose pocket prediction) > 3 : Do you want to find conserved pockets among homologs?
>
> Concerning question 1, if you just need a method for a few structures<= br> > you can go for slower programs (mostly energy based algorithms) like > SiteMap from Schr=F6dinger (but you need a license) Q-SiteFinder or > PocketPicker or Vice (I think it's sold by Tripos) There are surel= y more
> than that.
> If you need to process a large number of structures, considering
> geometry based methods might become an interesting choice. Choices cou= ld
> be Ligsite, fpocket, PASS, SiteFinder (included in MOE by CCG) ...
>
> Regarding question 2. Pocket prediction is not equal drug binding site=
> prediction. Recent druggability prediction methods have been published=
> and some scores are available ready for use in SiteMap (I don't kn= ow if
> you still have to calculate it or if they finally included it into the=
> SiteMap distribution) and fpocket. I suspect also QSiteFinder might gi= ve
> indications on druggability (I extrapolate from the methodology I just=
> read very quickly, so maybe I'm wrong here ;) ).
>
> Regarding question 3, I think ligsite csc can help there
> (http://projects.biotec.tu-dresden.de/pocket/), or else hpocket, w= hich
> is part of the fpocket webserver :
> http://bioserv.rpbs.univ-paris-diderot.fr/fpocket/
>
> I hope that this gives you at least a direction, there are really lots=
> of methods and it is indeed not easy to know which one to use ;)
>
> Ah, I nearly forgot, metapocket2.0 is a sort of consensus pocket
> prediction method that makes use of LIGSITEcsc, PASS, Q-SiteFinder, > SURFNET, Fpocket, GHECOM and ConCavity. This has again advantages and<= br> > disadvantages, but well, at least you know that it exists ;)
>
> Good luck.
>
> Peter Schmidtke
>
>
>
>
> On 12/11/2010 06:44 PM, Deepangi Pandit deepangi.pandit~!~gmail.com wrote:
>> Sent to CCL by: Deepangi Pandit [deepangi.pandit(!)gmail.com]
>> Dear All:
>> I tried to search literature and Internet to find a reliable metho= d
>> that I can use to identify protein-ligand binding site. I came acr= oss
>> number of papers but I am unable to evaluate the methods before I<= br> >> start using them. I was also unable to find a review which compare= s
>> the methods. It seems method can be broadly classified as "Ge= ometry
>> based" and "Energy Based". Could you please recomme= nd from your own
>> experience which method gives reasonable results. Also, feel free = to
>> share pros and cons of the method.
>>
>> Thank you.
>> Deepa
>>
>> List of methods I came across
>>
>> Q-Site Finder
>> http://www.bioinformatics.leeds.ac.uk/qsitefinder
>>
>> Surface triplet propensities
>> http://= opus.bch.ed.ac.uk/stp
>>
>> Screen
>> http://interface.bioc.columbia.edu/screen> =A0 =A0 =A0http= ://www.ccl.net/cgi-bin/ccl/send_ccl_message> =A0 =A0 =A0http://ww= w.ccl.net/cgi-bin/ccl/send_ccl_message> =A0 =A0 =A0http://www.ccl.ne= t/chemistry/sub_unsub.shtml> =A0 =A0 =A0http://www.ccl.net/spammers.txt> >
>



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