From owner-chemistry@ccl.net Fri Oct 16 12:00:01 2020 From: "Mark Mackey mark_._cresset-group.com" To: CCL Subject: CCL: Pharmacophore flexible search tool Message-Id: <-54186-201015044129-14773-3kM/pz5UP4wgxvIMYxTJwA[a]server.ccl.net> X-Original-From: Mark Mackey Content-Language: en-US Content-Type: multipart/alternative; boundary="_000_DBBPR08MB4235A669353C522DB83D515597020DBBPR08MB4235eurp_" Date: Thu, 15 Oct 2020 08:41:15 +0000 MIME-Version: 1.0 Sent to CCL by: Mark Mackey [mark===cresset-group.com] --_000_DBBPR08MB4235A669353C522DB83D515597020DBBPR08MB4235eurp_ Content-Type: text/plain; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Hi Doug, The main advantage of pharmacophore methods over more accurate 3D ligand si= milarity comparisons is speed: you can preprocess the database to generate = conformations and then searching that database is extremely fast. Once you = allow the method to change conformations you then have to be able to evalua= te the energy of those conformations (or else it will just find ridiculousl= y high-energy "matches") and that is always going to be slow. Docking metho= ds are more-or-less forced to do this because they generally use very hard = van der Waals interactions with the protein so that if a conformation is a = quarter of an Angstrom out its docking score can increase significantly. Th= at's not true for pharmacophore methods, where in general minor conformatio= n change on a molecule matching the pharmacophore won't make it lose the ma= tch. Even the more accurate 3D ligand similarity methods such as Phase shape, RO= CS or our shape/electrostatic similarity methods in Blaze and Forge (which,= quick plug, are free for graduate students to use!) tend to rely on precom= puted conformations as it is generally significantly more efficient and add= ing ligand flexibility does not improve the results. There are exceptions: FlexS from BioSolveIT and the eSim method from the Ja= in group both (I believe) incorporate a measure of ligand flexibility (the = latter only for fine-tuning after initially processing a conformer ensemble= ), but neither is free as far as I am aware. Is there a reason why you believe you need flexibility during the match its= elf? Regards, Mark -- Mark Mackey Chief Scientific Officer Cresset New Cambridge House, Bassingbourn Road, Litlington, Cambridgeshire, SG8 0SS= , UK tel: +44 (0)1223 858890 mobile: +44 (0)7595 099165 fax: +44 (0)1223 8= 53667 email: mark-$-cresset-group.com web: www.cr= esset-group.com skype: mark_cresset > From: owner-chemistry+mark=3D=3Dcresset-bmd.com-$-ccl.net On Behalf Of HOUSTON Douglas DouglasR.Hous= ton[#]ed.ac.uk Sent: 15 October 2020 07:45 To: Mark Mackey Subject: CCL: Pharmacophore flexible search tool Hi Sergio, Thanks for your reply. Do you know the details of how ZINCPharmer compares = the molecules in the database with the pharmacophore? I note this from the = site: "The ZincPharmer search technology uses the Pharmer open source pharmacophore search technology to efficient= ly search a large database of fixed conformers for pharmacophore matches" There's a difference between creating a conformer library, and actually tre= ating each molecule as flexible. I already have ways of creating conformer libraries, but what results is a = coarse sampling of all possible conformations. What I'm looking for is a wa= y of treating the library compounds as actually flexible, in the same way t= hat e.g. Vina or Autodock treats the small molecule to be docked into a rec= eptor as flexible. Regards, Doug ________________________________ > From: owner-chemistry+douglasr.houston=3D=3Ded.ac.uk-*-ccl.net on behalf of Sergio Vechi ve= chism/agmail.com Sent: 19 May 2020 21:59 To: HOUSTON Douglas Subject: CCL: Pharmacophore flexible search tool Dear Doug, You can build the pharmacophore model with PharmaGist (https://bioinfo3d.cs= .tau.ac.il/PharmaGist/php.php) and search Zinc database using ZINCPharmer (= http://zincpharmer.csb.pitt.edu/). Cheers, Sergio +--------------------------------------------------------------------------= --------------------------------------+ Dr. S=E9rgio Vechi | vechism:gmail.com Associate Professor Federal University of Alagoas | Campus Arapiraca | NCEx Av. Manuel Severino Barbosa, s/n, Bom Sucesso 57309-005 Arapiraca (AL) - Brazil +--------------------------------------------------------------------------= --------------------------------------+ On Tue, May 19, 2020 at 4:35 PM HOUSTON Douglas DouglasR.Houston]![ed.ac.uk= > wrote: Hi all, Does anyone know of a free (for academics at least) chemical search tool, t= hat will screen a large compound library (say an SDF of 100,000 molecules) = against a reference pharmacophore/ligand, and treat the library compounds a= s flexible and not rigid? I've asked this before but for some reason the formatting was so screwed up= I don't think most people could read it! Regards, Doug ---------------------------------------------------------------------------= --------------- Dr. Douglas R. Houston Senior Lecturer in Computational Biochemistry Institute of Quantitative Biology, Biochemistry and Biotechnology Room 2.12, Waddington 1 Building King's Buildings University of Edinburgh Edinburgh, EH9 3BF, UK Tel. 07986875743 The University of Edinburgh is a charitable body, registered in Scotland, w= ith registration number SC005336. --_000_DBBPR08MB4235A669353C522DB83D515597020DBBPR08MB4235eurp_ Content-Type: text/html; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable

Hi Doug,<= o:p>

&nbs= p;

The main = advantage of pharmacophore methods over more accurate 3D ligand similarity = comparisons is speed: you can preprocess the database to generate conformat= ions and then searching that database is extremely fast. Once you allow the method to change conformations you t= hen have to be able to evaluate the energy of those conformations (or else = it will just find ridiculously high-energy “matches”) and that = is always going to be slow. Docking methods are more-or-less forced to do this because they generally use very hard va= n der Waals interactions with the protein so that if a conformation is a qu= arter of an Angstrom out its docking score can increase significantly. That= ’s not true for pharmacophore methods, where in general minor conformation change on a molecule matching the phar= macophore won’t make it lose the match.

&nbs= p;

Even the = more accurate 3D ligand similarity methods such as Phase shape, ROCS or our= shape/electrostatic similarity methods in Blaze and Forge (which, quick pl= ug, are free for graduate students to use!) tend to rely on precomputed conformations as it is generally signifi= cantly more efficient and adding ligand flexibility does not improve the re= sults.

&nbs= p;

There are= exceptions: FlexS from BioSolveIT and the eSim method from the Jain group = both (I believe) incorporate a measure of ligand flexibility (the latter on= ly for fine-tuning after initially processing a conformer ensemble), but neither is free as far as I am aware.

&nbs= p;

Is there = a reason why you believe you need flexibility during the match itself?=

 

Regards,

Mark

 

--

Mark Mackey

Chief Scientific Officer

Cresset

New Cambridge House, Bassingbourn Road, Litlington, Cambridgeshire= , SG8 0SS, UK

tel: +44 (0)1223 858890    mobile: +44 (0)7595= 099165    fax: +44 (0)1223 853667

email: mark-$-cress= et-group.com    web: www.cresset-group.com&n= bsp;   skype: mark_cresset

 

&nbs= p;

&nbs= p;

From: owner-chemistry+mark=3D=3Dcresset-bmd.com-$-ccl.net <owner-che= mistry+mark=3D=3Dcresset-bmd.com-$-ccl.net> On Behalf Of HOUSTON Douglas DouglasR.Houston[#]ed.ac.uk
Sent: 15 October 2020 07:45
To: Mark Mackey <mark-$-cresset-group.com>
Subject: CCL: Pharmacophore flexible search tool

 

Hi Serg= io,

&n= bsp;

Thanks = for your reply. Do you know the details of how ZINCPharmer compares the mol= ecules in the database with the pharmacophore? I note this from the site:

&n= bsp;

"<= /span>The ZincPharmer search technology uses th= e Pharmer open source pharmacophore search technology to efficiently search a large datab= ase of fixed conformers for pharmacophore matches"

&n= bsp;

There's a difference between creating a conformer library, and ac= tually treating each molecule as flexible.

&n= bsp;

I already have ways of creating conformer libraries, but what res= ults is a coarse sampling of all possible conformations. What I'm looking f= or is a way of treating the library compounds as actually flexible, in the same way that e.g. Vina or A= utodock treats the small molecule to be docked into a receptor as flexible.=

&n= bsp;

Regards,=

Doug

 

&n= bsp;

From: owner-chemistry+douglasr.houston=3D=3Ded.ac.uk-*-cc= l.net <owner-chemistry+douglasr.houston=3D=3Ded.ac.uk-*-ccl.net> on b= ehalf of Sergio Vechi vechism/agmail.com <owner-chemistry-*-ccl.net><= br> Sent: 19 May 2020 21:59
To: HOUSTON Douglas <DouglasR.Houston-*-ed.ac.uk>
Subject: CCL: Pharmacophore flexible search tool <= /p>

 

= Dear Doug,

=  

= You can build the pharmacophore model with PharmaGist (https://bioinfo3d.cs.tau.ac.il/Ph= armaGist/php.php) and search Zinc database using ZINCPharmer (http://zincpharm= er.csb.pitt.edu/).

=  

= Cheers,

=  

= Sergio

+-----------------------= ---------------------------------------------------------------------------= --------------+
   Dr. S=E9rgio Vechi | vechism:gmail.com           =                     &nbs= p;  
     Associate Professor
     Federal University of Alagoas | Campus Arapiraca |= NCEx

     Av. = Manuel Severino Barbosa, s/n, Bom Sucesso

    = 57309-005 Arapiraca (AL) - Brazil           =             
+--------------------------------------------------------------------------= --------------------------------------+

 

 

On Tue, May 19, 2020 at 4:35 PM HOUSTON Douglas Doug= lasR.Houston]![ed.ac.uk <owner-chemistry|,|ccl.net> wrote:=

Hi all,

&n= bsp;

Does anyone know of a free (for academics at= least) chemical search tool, that will screen a large compound l= ibrary (say an SDF of 100,000 molecules) against a reference pharmacophore/ligand, and treat the library compounds as flexi= ble and not rigid?=

&n= bsp;

I've asked this before but for some reason t= he formatting was so screwed up I don't think most people could read it!

&n= bsp;

Regards,

Doug

&n= bsp;

--------------------------------------------= ----------------------------------------------

Dr. Douglas R. Houston

Senior Lecturer in Computational Biochemistry

Institute of Quantitative Biology, Biochemistry and Biotechnology=

Room 2.12, Waddington 1 Building

King's Buildings

University of Edinburgh

Edinburgh, EH9 3BF, UK

Tel. 07986875743

&n= bsp;

The University of Edinburgh is a charitable body, re= gistered in Scotland, with registration number SC005336.

--_000_DBBPR08MB4235A669353C522DB83D515597020DBBPR08MB4235eurp_-- From owner-chemistry@ccl.net Fri Oct 16 12:35:01 2020 From: "Gareth Jones java.jones::gmail.com" To: CCL Subject: CCL: Pharmacophore flexible search tool Message-Id: <-54187-201015233721-1100-jmC5amjH/vMHP7/N2KHJWQ-.-server.ccl.net> X-Original-From: Gareth Jones Content-Language: en-US Content-Type: multipart/alternative; boundary="------------CFBEE8BABE5C7A14E99A8A4E" Date: Thu, 15 Oct 2020 21:37:12 -0600 MIME-Version: 1.0 Sent to CCL by: Gareth Jones [java.jones:+:gmail.com] This is a multi-part message in MIME format. --------------CFBEE8BABE5C7A14E99A8A4E Content-Type: text/plain; charset=windows-1252; format=flowed Content-Transfer-Encoding: 8bit Hi Doug, I have ownership of the code used in GAPE (J. Chem. Inf. Model. 2010, 50, 11, 2001–2018) which is a pharmacophore elucidation program that will also perform fully flexible search of a library against a pharmacophore- though it is pretty slow so 100K compounds may be pushing it.  The software is an improvement of the Tripos GASP program (Jones, G., Willett, P. & Glen, R.C., Journal of Computer-Aided Molecular Design, 9, 1995, 532). If you want to use it for academic research I can give you a copy. Cheers, Gareth Jones On 10/15/2020 12:44 AM, HOUSTON Douglas DouglasR.Houston[#]ed.ac.uk wrote: > Hi Sergio, > > Thanks for your reply. Do you know the details of how ZINCPharmer > compares the molecules in the database with the pharmacophore? I note > this from the site: > > "The ZincPharmer search technology uses thePharmer > open source pharmacophore > search technology to efficiently search a large database of *fixed > conformers* for pharmacophore matches" > > There's a difference between creating a conformer library, and > actually treating each molecule as flexible. > > I already have ways of creating conformer libraries, but what results > is a coarse sampling of all possible conformations. What I'm looking > for is a way of treating the library compounds as *actually flexible*, > in the same way that e.g. Vina or Autodock treats the small molecule > to be docked into a receptor as flexible. > > Regards, > Doug > > > ------------------------------------------------------------------------ > *From:* owner-chemistry+douglasr.houston==ed.ac.uk-*-ccl.net > on behalf of > Sergio Vechi vechism/agmail.com > *Sent:* 19 May 2020 21:59 > *To:* HOUSTON Douglas > *Subject:* CCL: Pharmacophore flexible search tool > Dear Doug, > > You can build the pharmacophore model with PharmaGist > (https://bioinfo3d.cs.tau.ac.il/PharmaGist/php.php) and search Zinc > database using ZINCPharmer (http://zincpharmer.csb.pitt.edu/). > > Cheers, > > Sergio > +----------------------------------------------------------------------------------------------------------------+ >    Dr. Sérgio Vechi | /vechism:gmail.com / >      Associate Professor >      Federal University of Alagoas | Campus Arapiraca | NCEx >      Av. Manuel Severino Barbosa, s/n, Bom Sucesso > 57309-005 Arapiraca (AL) - Brazil > +----------------------------------------------------------------------------------------------------------------+ > > > On Tue, May 19, 2020 at 4:35 PM HOUSTON Douglas > DouglasR.Houston]![ed.ac.uk > > wrote: > > Hi all, > > Does anyone know of a free (for academics at least) chemical > search tool, that will screen a large compound library (say an SDF > of 100,000 molecules) against a reference pharmacophore/ligand, > and treat the library compounds as flexible and not rigid? > > I've asked this before but for some reason the formatting was so > screwed up I don't think most people could read it! > > Regards, > Doug > > ------------------------------------------------------------------------------------------ > Dr. Douglas R. Houston > Senior Lecturer in Computational Biochemistry > Institute of Quantitative Biology, Biochemistry and Biotechnology > Room 2.12,Waddington 1 Building > King's Buildings > University of Edinburgh > Edinburgh,EH9 3BF, UK > Tel. 07986875743 > > The University of Edinburgh is a charitable body, registered in > Scotland, with registration number SC005336. > --------------CFBEE8BABE5C7A14E99A8A4E Content-Type: text/html; charset=windows-1252 Content-Transfer-Encoding: 8bit


Hi Doug,

I have ownership of the code used in GAPE (J. Chem. Inf. Model. 2010, 50, 11, 2001–2018) which is a pharmacophore elucidation program that will also perform fully flexible search of a library against a pharmacophore- though it is pretty slow so 100K compounds may be pushing it.  The software is an improvement of the Tripos GASP program (Jones, G., Willett, P. & Glen, R.C.,  Journal of Computer-Aided Molecular Design, 9, 1995, 532).

If you want to use it for academic research I can give you a copy.


Cheers,

Gareth Jones


On 10/15/2020 12:44 AM, HOUSTON Douglas DouglasR.Houston[#]ed.ac.uk wrote:
Hi Sergio,

Thanks for your reply. Do you know the details of how ZINCPharmer compares the molecules in the database with the pharmacophore? I note this from the site:

"The ZincPharmer search technology uses the Pharmer open source pharmacophore search technology to efficiently search a large database of fixed conformers for pharmacophore matches"

There's a difference between creating a conformer library, and actually treating each molecule as flexible.

I already have ways of creating conformer libraries, but what results is a coarse sampling of all possible conformations. What I'm looking for is a way of treating the library compounds as actually flexible, in the same way that e.g. Vina or Autodock treats the small molecule to be docked into a receptor as flexible.

Regards,
Doug


From: owner-chemistry+douglasr.houston==ed.ac.uk-*-ccl.net <owner-chemistry+douglasr.houston==ed.ac.uk-*-ccl.net> on behalf of Sergio Vechi vechism/agmail.com <owner-chemistry-*-ccl.net>
Sent: 19 May 2020 21:59
To: HOUSTON Douglas <DouglasR.Houston-*-ed.ac.uk>
Subject: CCL: Pharmacophore flexible search tool
 
Dear Doug,

You can build the pharmacophore model with PharmaGist (https://bioinfo3d.cs.tau.ac.il/PharmaGist/php.php) and search Zinc database using ZINCPharmer (http://zincpharmer.csb.pitt.edu/).

Cheers,

Sergio
+----------------------------------------------------------------------------------------------------------------+
   Dr. Sérgio Vechi | vechism:gmail.com                                   
     Associate Professor
     Federal University of Alagoas | Campus Arapiraca | NCEx
     Av. Manuel Severino Barbosa, s/n, Bom Sucesso
     57309-005 Arapiraca (AL) - Brazil                        
+----------------------------------------------------------------------------------------------------------------+


On Tue, May 19, 2020 at 4:35 PM HOUSTON Douglas DouglasR.Houston]![ed.ac.uk <owner-chemistry|,|ccl.net> wrote:
Hi all,

Does anyone know of a free (for academics at least) chemical search tool, that will screen a large compound library (say an SDF of 100,000 molecules) against a reference pharmacophore/ligand, and treat the library compounds as flexible and not rigid?

I've asked this before but for some reason the formatting was so screwed up I don't think most people could read it!

Regards,
Doug

------------------------------------------------------------------------------------------
Dr. Douglas R. Houston
Senior Lecturer in Computational Biochemistry
Institute of Quantitative Biology, Biochemistry and Biotechnology
Room 2.12, Waddington 1 Building
King's Buildings
University of Edinburgh
Edinburgh, EH9 3BF, UK
Tel. 07986875743

The University of Edinburgh is a charitable body, registered in Scotland, with registration number SC005336.
--------------CFBEE8BABE5C7A14E99A8A4E--