From owner-chemistry@ccl.net Thu Mar 3 10:42:00 2016 From: "Andrey Voronkov av+/-digitalbiopharm.com" To: CCL Subject: CCL: Pharmacophore: a question of semantics Message-Id: <-52094-160303095320-24342-849Rw5RI+rRObhDHX26I+Q]_[server.ccl.net> X-Original-From: Andrey Voronkov Content-Type: multipart/alternative; boundary=089e01537ea26073e4052d262867 Date: Thu, 3 Mar 2016 17:52:53 +0300 MIME-Version: 1.0 Sent to CCL by: Andrey Voronkov [av * digitalbiopharm.com] --089e01537ea26073e4052d262867 Content-Type: text/plain; charset=UTF-8 Dear Fabrizio, you are right. This is common pharmacophore and reviewer mixes it with 3D-QSAR. Pharmacophore, by the definition is the feature, which is required for binding with protein. Negative molecules should not be taken into account. PS Our company is interested in pharmacophore models, like common pharmacophores and common pharmacophores, coupled to molecular dynamics. If anyone is interested in these topics - please let me know. Best regards, Andrey On Thu, Mar 3, 2016 at 10:54 AM, Fabrizio Manetti fabrizio.manetti!A! unisi.it wrote: > > Sent to CCL by: "Fabrizio Manetti" [fabrizio.manetti===unisi.it] > Dear All, > I'm writing to ask you for advice on a dispute on a matter of method > definition. > Very recently, I submitted a manuscript for publication describing a > pharmacophoric model built using only two active compounds. The goal was to > generate a superposition model aimed at finding common chemical features > shared by the molecules (i.e., a common pharmacopore), as one can do by > using HipHop or Phase softwares. > > Unexpectedly, I received the following reply from one of the reviewers: > > "A pharmacophore model is a hypothesis accounting for the observed > biological activities of a set of molecules that bind to a common > biological target. This model is developed by measuring the activity of > multiple analogues (generally libraries of 50 or more compounds), > determining the least-energy conformer for each analogue, and then > superimposing these conformers. The computer algorithm then uses these data > and the activity data to generate a pharmacophore that is hypothetical, and > that can be further refined when additional data are gathered. In order to > determine an accurate pharmacophore model, both active and inactive > compounds must be evaluated, and the model should be able to account for > differences in activity across a range of molecules. It would be lucky > indeed to be able to determine a pharmacophore from 2 molecules, and > impossible to generate a pharmacophore from one molecule. (...) Thus, it is > a question of semantics. If the authors insist on calling their mod! > el based on 2 compounds a pharmacophore, the paper should be rejected. If > they remove references to a pharmacophore and state instead that the > molecules were designed from "visual inspection and chemical expertise", > then it should be published." > > It seems to me that what the reviewer is describing is indeed a 3D QSAR > pharmacophoric model, which is not what we describe and claim in the paper. > > Therefore, I would like to ask for advice on the most appropriate > definition for such a model based on superposing a few compounds and > looking at their common chemical features. Is the term "pharmacophore" > still correct in your opinion, or a different word should be used instead? > > Thank you for your opinion. > Regards,> > > -- Sincerely yours, Andrey Voronkov, PhD Founder & Executive director DigitalBioPharm ltd. Tel: +47 46 22 77 96 av]*[digitalbiopharm.com www.digitalbiopharm.com --089e01537ea26073e4052d262867 Content-Type: text/html; charset=UTF-8 Content-Transfer-Encoding: quoted-printable
Dear Fabrizio, you are right. This is common pharmacophore= and reviewer mixes it with 3D-QSAR. Pharmacophore, by the definition is th= e feature, which is required for binding with protein. Negative molecules s= hould not be taken into account.

PS Our company is inter= ested in pharmacophore models, like common pharmacophores and common pharma= cophores, coupled to molecular dynamics. If anyone is interested in these t= opics - please let me know.

Best regards,
= Andrey

On Thu, Mar 3, 2016 at 10:54 AM, Fabrizio Manetti fabrizio.manetti!A= !unisi.it <owner-chemistry]*[ccl.net> wrote:

Sent to CCL by: "Fabrizio=C2=A0 Manetti" [fabrizio.manetti=3D=3D= =3Dunisi.i= t]
Dear All,
I'm writing to ask you for advice on a dispute on a matter of method de= finition.
Very recently, I submitted a manuscript for publication describing a pharma= cophoric model built using only two active compounds. The goal was to gener= ate a superposition model aimed at finding common chemical features shared = by the molecules (i.e., a common pharmacopore), as one can do by using HipH= op or Phase softwares.

Unexpectedly, I received the following reply from one of the reviewers:

"A pharmacophore model is a hypothesis accounting for the observed bio= logical activities of a set of molecules that bind to a common biological t= arget. This model is developed by measuring the activity of multiple analog= ues (generally libraries of 50 or more compounds), determining the least-en= ergy conformer for each analogue, and then superimposing these conformers. = The computer algorithm then uses these data and the activity data to genera= te a pharmacophore that is hypothetical, and that can be further refined wh= en additional data are gathered. In order to determine an accurate pharmaco= phore model, both active and inactive compounds must be evaluated, and the = model should be able to account for differences in activity across a range = of molecules. It would be lucky indeed to be able to determine a pharmacoph= ore from 2 molecules, and impossible to generate a pharmacophore from one m= olecule. (...) Thus, it is a question of semantics. If the authors insist o= n calling their mod!
=C2=A0el based on 2 compounds a pharmacophore, the paper should be rejected= . If they remove references to a pharmacophore and state instead that the m= olecules were designed from "visual inspection and chemical expertise&= quot;, then it should be published."

It seems to me that what the reviewer is describing is indeed a 3D QSAR pha= rmacophoric model, which is not what we describe and claim in the paper.
Therefore, I would like to ask for advice on the most appropriate definitio= n for such a model based on superposing a few compounds and looking at thei= r common chemical features. Is the term "pharmacophore" still cor= rect in your opinion, or a different word should be used instead?

Thank you for your opinion.
Regards,



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--
Sincerely yours,
Andrey Voronkov, PhD
Founder &a= mp; Executive director

DigitalBioPharm ltd.
Tel: +47 46 22 77 96<= br>av]*[digitalbi= opharm.com
www.digitalbiopharm.com
--089e01537ea26073e4052d262867--