I suggest you look at OMEGA from OpenEye (http://www.eyesopen.com/omega). It is highly configur= able in terms of search resolution and filtering.

Joe

From: = "Bin Sun sunbinxod*gmail.com" <owner-chemistry:+:ccl.net>
Reply-To: CCL Subscribers <chemistry:+:ccl.net>
Date: Friday, July 5, 2013 11:01 PM
To: <= /span> Joseph Corkery <jcorkery= :+:eyesopen.com>
Subject: = CCL: Tool to generate conformer database for ligand_like molecules

Hello Everyone,

I want to achieve all the possible conformations c= orresponding to the minimums on the potential surface of a ligand_like mole= cule.

To this end, I f= irstly need to generate as many as possible conformers by rotating the rota= table bonds via some tools or software; Secondly, A sifting stage is perfor= med in which the "bad" conformers having unfavorable energies are excluded. To ensure that there are no important conformations being omitted. the con= former database generated in the first step must be as completed as p= ossible.

Is there any = tool or software that can generate completed conformer database for ligand_= like molecules ?

Thank= s !

-Sun

--_000_CE00413E2E052jcorkeryeyesopencom_-- From owner-chemistry@ccl.net Mon Jul 8 12:28:00 2013 From: "Paul Elsinghorst paul.elsinghorst[-]uni-bonn.de" To: CCL Subject: CCL: Tool to generate conformer database for ligand_like molecules Message-Id: <-48901-130708090539-19702-NkwMEB7grXTq9gWizr6tHQ],[server.ccl.net> X-Original-From: Paul Elsinghorst Content-Type: multipart/alternative; boundary=047d7bf0cefeee334804e0ffb249 Date: Mon, 8 Jul 2013 15:05:30 +0200 MIME-Version: 1.0 Sent to CCL by: Paul Elsinghorst [paul.elsinghorst|uni-bonn.de] --047d7bf0cefeee334804e0ffb249 Content-Type: text/plain; charset=ISO-8859-1 Content-Transfer-Encoding: quoted-printable Confab might be worth a try: http://docs.confab.googlecode.com/hg/index.html Dr. Paul Elsinghorst Pharmazeutisches Institut der Universit=E4t Bonn Pharmazeutische Chemie I An der Immenburg 4 53121 Bonn On Sat, Jul 6, 2013 at 5:01 AM, Bin Sun sunbinxod*gmail.com < owner-chemistry*|*ccl.net> wrote: > Hello Everyone, > > I want to achieve all the possible conformations corresponding to the > minimums on the potential surface of a ligand_like molecule. > > To this end, I firstly need to generate as many as possible conformers b= y > rotating the rotatable bonds via some tools or software; Secondly, A > sifting stage is performed in which the "bad" conformers having unfavorab= le > energies are excluded. To ensure that there are no important conformation= s > being omitted. the conformer database generated in the first step must b= e > as completed as possible. > > Is there any tool or software that can generate completed conformer > database for ligand_like molecules ? > > Thanks ! > > -Sun > --047d7bf0cefeee334804e0ffb249 Content-Type: text/html; charset=ISO-8859-1 Content-Transfer-Encoding: quoted-printable

Confab might be worth a try:

http://docs.confab.googlecode.com/hg/= index.html

<= div dir=3D"ltr">

Dr. Paul Elsinghorst

Pharmazeutisch= es Institut der Universit=E4t Bonn

Pharmazeutische Chemie I
An der Immenburg 4

53121 Bonn

On Sat, Jul 6, 2013 at 5:01 AM, Bin Sun = sunbinxod*gmail.com <= owner-chemistr= y*|*ccl.net> wrote:

Hello Everyone,

I want to achieve all the possible conformations corresponding to the min= imums on the potential surface of a ligand_like molecule.

=A0To this end, I firstly need to generate as many as p= ossible conformers by rotating the rotatable bonds via some tools or softwa= re; Secondly, A sifting stage is performed in which the "bad" con= formers having unfavorable energies are excluded. To ensure that there are = no important conformations being omitted. the conformer database generated = in the first step must =A0be as completed as possible.=A0

Is there any tool or software that can generate complet= ed conformer database for ligand_like molecules ?

Thanks !

-Sun

--047d7bf0cefeee334804e0ffb249-- From owner-chemistry@ccl.net Mon Jul 8 16:11:00 2013 From: "David A Case case ~~ biomaps.rutgers.edu" To: CCL Subject: CCL: Comparison of Experimental and computational Binding Affinities Message-Id: <-48902-130708085119-11730-u4RJAosW+wpzDaD2/pxYvw^server.ccl.net> X-Original-From: David A Case Content-Disposition: inline Content-Type: text/plain; charset=us-ascii Date: Mon, 8 Jul 2013 08:51:09 -0400 Mime-Version: 1.0 Sent to CCL by: David A Case [case{=}biomaps.rutgers.edu] On Sun, Jul 07, 2013, Hao-Bo Guo guohaobo::gmail.com wrote: > > I have two points on this type [MM-PBSA] of calculations: 1. The absolute > values are always useless, and only the relative binding affinities > or binding free energies are meaningful (owing to valuable error > cancelation etc); I'd like to argue for the opposite conclusion: relative affinities are often of little value: statisical errors may be large relative to the small energy differences being examined, and systematic errors arising > from the intrinsic solvent model (and the underlying force field itself) differ from one ligand to the next. On the other hand, estimates of the absolute affinities can be helpful in assessing the physical reality of the calculations, and their sensitivity to assumptions in the model. If the MM-PBSA estimate of the absolute affinity is wrong (especially if it is wrong by a large amount), something important might be missing from the model, such as changes in protonation state (or the wrong protonation states), ion binding or release that accompanies ligand binding, conformational relaxation not captured by the simulation, and so on. Of course, in practice, useful SAR's can often be generated from quite imperfect inputs. But these should be (mostly) judged by their predictive power and less by the ability to reproduce some binding energy differences that are already known. ...dave case From owner-chemistry@ccl.net Mon Jul 8 17:36:01 2013 From: "Hao-Bo Guo guohaobo-.-gmail.com" To: CCL Subject: CCL: Comparison of Experimental and computational Binding Affinities Message-Id: <-48903-130708145257-6880-rNabDCjNpjqL7SYZZ8JKWQ+*+server.ccl.net> X-Original-From: Hao-Bo Guo Content-Type: multipart/alternative; boundary=047d7b15b16106d1ee04e1048dfc Date: Mon, 8 Jul 2013 14:52:48 -0400 MIME-Version: 1.0 Sent to CCL by: Hao-Bo Guo [guohaobo:+:gmail.com] --047d7b15b16106d1ee04e1048dfc Content-Type: text/plain; charset=ISO-8859-1 I did not see your formula. It may be doable using MMPBSA to compare the binding affinity of different ligands, however, I'm not aware how it can be used to handle the concentration effects. Hao-Bo Guo On Sun, Jul 7, 2013 at 3:09 PM, Kshatresh Dutta Dubey kshatresh{:}gmail.com wrote: > Dear Guo, > > Thanks for your reply. However, if I change 1.6nM, 0.6nM, 10 nM, in > Kcal/mol using above formula, the difference in energy values are very > small. But the results of MMPBSA show difference of almost 05-10 kcal/mol > that means a large difference in kd values. So, can I compare the relative > binding affinities of these drugs using MMPBSA? > > Thanks > kdd > > > On Sun, Jul 7, 2013 at 10:32 PM, Hao-Bo Guo guohaobo::gmail.com -ccl.net> wrote: > >> Dear Kshatresh, >> >> I have two points on this type of calculations: 1. The absolute values >> are always useless, and only the relative binding affinities or binding >> free energies are meaningful (owing to valuable error cancelation etc); and >> 2. You definitely need to systematically benchmark your method prior to the >> calculations. >> >> Good luck, >> Hao-Bo Guo >> >> >> On Sun, Jul 7, 2013 at 12:30 PM, Kshatresh Dutta Dubey kshatresh:+: >> gmail.com wrote: >> >>> Dear All, >>> >>> I am very curious to know that whether the comparison of dissociation >>> constant (Kd values) with computationally calculated free energy is valid >>> or not. We often use DeltaG(binding)= -RTllnKd for this purpose. Suppose, I >>> have two different drug-protein complexes A and B where the binding energy >>> of A is more than B by 2.3 Kcal. This makes a difference of 50 fold in >>> dissociation constant scale. Okay, it looks fine in the context of theory. >>> However, in practical, if someone is using end point methods like MMPBSA or >>> LIE to calculate the binding free energy for different complexes, they >>> generally give error/difference of 4-5 kcal including entropy, that makes >>> 100-200 fold differences in scale of Kd values. >>> Now, my problem is that I have to compare affinity of five drugs >>> having Kd values 1.6, 0.67, 10, 36 and 25 nM using MMPBSA/LIE methods. Is >>> the comparison of binding affinity calculated by these methods(MMPBSA/LIE) >>> in reference to Kd values possible? >>> >>> -- >>> With best regards >>> >>> ******************************************************************************************************************* >>> Kshatresh Dutta Dubey, PhD >>> Post Doctoral Fellow >>> Indian Institute of Technology Kanpur >>> Kanpur, India >>> >>> >>> >> > > > -- > With best regards > > ******************************************************************************************************************* > Kshatresh Dutta Dubey, PhD > Post Doctoral Fellow > Indian Institute of Technology Kanpur > Kanpur, India > > > --047d7b15b16106d1ee04e1048dfc Content-Type: text/html; charset=ISO-8859-1 Content-Transfer-Encoding: quoted-printable

I did not see your formula. It may be doable using MM= PBSA to compare the binding affinity of different ligands, however, I'm= not aware how it can be used to handle the concentration effects.

Hao-Bo Guo

On Sun, Jul 7, 2013 at 3:09 PM, Kshatresh Dutta Dub= ey kshatresh{:}gmail.com <owner-che= mistry=-=ccl.net> wrote:

Dear Guo,

Thanks for your reply. However, if I change 1.6nM, 0.6nM, 10 nM, in Kcal/= mol using above formula, the difference in energy values are very small. Bu= t the results of MMPBSA show difference of almost 05-10 kcal/mol that means= a large difference in kd values. So, can I compare the relative binding af= finities of these drugs using MMPBSA?=A0

Thanks
kdd

On Sun, Jul 7, 2013 at 10:32 PM, Hao= -Bo Guo guohaobo::gmail.com<= /a> <owner-chemistry- -ccl.net> wrote:

Dear Kshatresh,

I have two points on this type of calculations: 1. The absolute val= ues are always useless, and only the relative binding affinities or binding= free energies are meaningful (owing to valuable error cancelation etc); an= d 2. You definitely need to systematically benchmark your method prior to t= he calculations.

Good luck,
Hao-Bo Guo

On Sun, Jul 7, = 2013 at 12:30 PM, Kshatresh Dutta Dubey kshatresh:+:gmail.com <owner-chemistry:+:ccl.net> wrote:

Dear All,

=A0=A0 I am very curious to know that whether the comparison of dissociati= on constant (Kd values) with computationally calculated free energy is vali= d or not. We often use DeltaG(binding)=3D -RTllnKd for this purpose. Suppos= e, I have two different drug-protein complexes A and B where the binding en= ergy of A is more than B by 2.3 Kcal. This makes a difference of 50 fold=A0= in dissociation constant scale. Okay, it looks fine in the context of theo= ry. However, in practical, if someone is using end point methods like MMPBS= A or LIE to calculate the binding free energy for different complexes, they= generally give error/difference of 4-5=A0 kcal including entropy, that mak= es 100-200 fold differences in scale of Kd values.
=A0=A0 Now, my problem is that I have to compare affinity of five drugs hav= ing Kd values 1.6, 0.67, 10, 36 and 25 nM using MMPBSA/LIE methods. Is the = comparison of binding affinity calculated by these methods(MMPBSA/LIE) in r= eference to Kd values possible?=A0

--
With best regards
**************************************************************************= *****************************************
Kshatresh Dutta Dubey, PhD
Post Doctoral Fellow
Indian Institute of Technology Kanp= ur
Kanpur, India

=

With best regards

***************************************= ***************************************************************************= *
Kshatresh Dutta Dubey, PhD

Post Doctoral Fellow

Ind= ian Institute of Technology Kanpur

Kanpur, India

<= /div>

--047d7b15b16106d1ee04e1048dfc--