ADL: autodock Digest, Vol 56, Issue 17

jose correa corrjose at gmail.com
Fri Apr 10 08:25:55 PDT 2009


Hi
?
I used Autodock-4 for blind docking inside Trypanosoma Cruzi Trypanothione
Reductase (PDB 1AOG) and Telomerase reverse transcriptase?(PDB 3DU6) enzymes
and some of the docked compounds showed estimated free energy of binding
more than -70000000 Kcal/mole for the first 4 ranked conformers so is it a
logic or acceptable calculation or not ? and if it is acceptable what is the
explanation of this very?low energy ?. However, the 5th conformer showed
binding energy in a normal range around -5 to -10 Kcal/mole.
Please reply to me as soon as possible because my Ph.D.?supervisor Dr Aly
Hazzaa said that Autodock-4 is a bad software and?not working good. so
please reply to me on this problem because it will affect?my career badly.
?
Thank you
?
Yours,?

Mostafa El-Miligy

Dear Mostafa
I suggest you that first use autodock 3.0.5 to carry out your docking under
blind docking procedure. Then, you need to use these results to select the
flexible residues using ADT. If Autodock3 yield very negative free energy
values, you should check your 3-D target to verify any bad structural
(missinh atoms, residues etc) or test with other 3-D structure.
I hope it helps you
José Correa-Basurto

2009/4/10 <autodock-request at scripps.edu>

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> Today's Topics:
>
>   1.  Urgent for my Ph.D. thesis and my career (Mostafa El-Miligy)
>   2. Re:  error in constants.h (Mostafa El-Miligy)
>   3.  Any Advice? (Avni P Nimani)
>   4.  Interesting Finding (Avni P Nimani)
>   5. Re:  Urgent for my Ph.D. thesis and my career
>      (mswingle at jaguar1.usouthal.edu)
>   6. Re:  Autodock4 error !!! (Liu Ji)
>   7. Re:  Urgent for my Ph.D. thesis and my career (Gavin Seddon)
>   8. Re:  Urgent for my Ph.D. thesis and my career
>      (L. Michel Espinoza-Fonseca)
>
>
> ----------------------------------------------------------------------
>
> Message: 1
> Date: Thu, 9 Apr 2009 11:40:25 -0700 (PDT)
> From: Mostafa El-Miligy <melmiligy4m at yahoo.com>
> Subject: ADL: Urgent for my Ph.D. thesis and my career
> To: autodock at scripps.edu
> Message-ID: <241837.45054.qm at web35503.mail.mud.yahoo.com>
> Content-Type: text/plain; charset=iso-8859-1
>
> Hi
> ?
> I used Autodock-4 for blind docking inside Trypanosoma Cruzi Trypanothione
> Reductase (PDB 1AOG) and Telomerase reverse transcriptase?(PDB 3DU6) enzymes
> and some of the docked compounds showed estimated free energy of binding
> more than -70000000 Kcal/mole for the first 4 ranked conformers so is it a
> logic or acceptable calculation or not ? and if it is acceptable what is the
> explanation of this very?low energy ?. However, the 5th conformer showed
> binding energy in a normal range around -5 to -10 Kcal/mole.
> Please reply to me as soon as possible because my Ph.D.?supervisor Dr Aly
> Hazzaa said that Autodock-4 is a bad software and?not working good. so
> please reply to me on this problem because it will affect?my career badly.
> ?
> Thank you
> ?
> Yours,?
>
> Mostafa El-Miligy
> ?
>
> Mostafa El-Miligy
>
> Ph.D. student
> Department of Pharmaceutical Chemistry
> Faculty of Pharmacy
> University of Alexandria
> Egypt
>
>
>
>
>
> ------------------------------
>
> Message: 2
> Date: Thu, 9 Apr 2009 15:49:43 -0700 (PDT)
> From: Mostafa El-Miligy <melmiligy4m at yahoo.com>
> Subject: Re: ADL: error in constants.h
> To: autodock at scripps.edu
> Message-ID: <249312.85823.qm at web35502.mail.mud.yahoo.com>
> Content-Type: text/plain; charset=iso-8859-1
>
> Hi Sara
> ?
> Yes I have prepared the receptor by autogrid-4 and I have run the docking
> by autodock-4.0
> but 5 from 18 compounds docked in the trypanothione reductase enzyme?formed
> very low binding energy (in millions).
> If you have any explanation for that please tell me.
>
> Dr. Mostafa El-Miligy
>
> --- On Thu, 4/9/09, sarah karma <crimsonflower at gmail.com> wrote:
>
>
> From: sarah karma <crimsonflower at gmail.com>
> Subject: Re: ADL: error in constants.h
> To: autodock at scripps.edu
> Date: Thursday, April 9, 2009, 8:49 PM
>
>
> thank you but i've prepared every thing by autigrid 4 and autodock4.1!
> another idea?
> ________________________________________________
> --- ADL: AutoDock List? --- http://autodock.scripps.edu/mailing_list ---
>
>
>
>
>
> ------------------------------
>
> Message: 3
> Date: Thu, 9 Apr 2009 19:23:16 -0400 (EDT)
> From: Avni P Nimani <animani at nmu.edu>
> Subject: ADL: Any Advice?
> To: autodock at scripps.edu
> Message-ID: <4863051.1239319396640.JavaMail.animani at nmu.edu>
> Content-Type: text/plain; charset=UTF-8
>
>     I am a graduate student working on his thesis involving
> docking using AutoDock 4.0 and ran into an interesting circumstance.
> The docking of the ligand using a rigid body macromolecule gives a
> rather weak Ki of 10^-4 M; however, I made 5 residues flexible in the
> macromolecule binding pocket and the strength of the Ki increased to
> 10^-11 M.  Much of the binding energy is being contributed by internal
> energy.  I was wondering on how to deal with this consequence, as it
> seems that much of the increase in energy is a result of the flexible
> macrolecule residues as opposed to an increase in intermolecular
> interactions with the ligand.  What would you suggest?  And is there
> any references or literature available that addresses this issue or at
> least papers in which flexible macromolecule residues are used?  I only
> found one paper in PubMed that reported using four flexible
> macromolecule residues, but I don't think they reported how they dealt
> with the internal energy issues.
>           The protein was generated by homology modeling.  The
> structure was minimized by L-BFGS method to RMS of 0.1.  The gradient
> of 0.1 was chosen simply because the desired effect was to leave the
> model as close to crystallographic data as possible, in which major
> problems such as bond distances were fixed.  The minimized model was
> assessed for peculiarities by PROCHECK, in which the model was found to
> have no steric clashes and 99% of residues were in allowed
> conformational regions.  The final receptor protein conformation was
> highly energetically favorable.
>         Flexible receptor docking without a ligand is not possible
> since nothing is actually docking.  The rigid receptor docking shows
> the internal energy due to the ligand to be small relative to the
> intramolecular energies.  This control serves the purpose of comparison
> the best because you can approximate how much contribution to the
> internal is coming from the flexible residues in the binding pocket as
> opposed to the ligand.  I appreciate advice anyone can provide
> regarding this issue knowing that the residues of interest are not
> clashing.
>
>                                       Sincerely,
>                                                  Avni
>
>
>
> ------------------------------
>
> Message: 4
> Date: Thu, 9 Apr 2009 19:27:07 -0400 (EDT)
> From: Avni P Nimani <animani at nmu.edu>
> Subject: ADL: Interesting Finding
> To: autodock at scripps.edu
> Message-ID: <3571994.1239319627750.JavaMail.animani at nmu.edu>
> Content-Type: text/plain; charset=UTF-8
>
> Does anybody know how to account for the additional internal energy
> that occurs when flexible residues are incorporated in the binding
> pocket of the receptor?  The AutoDock4/ADT tutorial uses only two
> flexible residues, perhaps to help limit the internal energy term.
> Also, perhaps using two flexible residues of primary importance to
> ligand docking gives the most accurate Ki for docking models.  A paper
> recently published in 2008 used four flexible residues in the receptor
> binding pocket and reported the free energy change as is.  The
> contribution of the internal energy from these receptor residues can be
> quite significant.  Currently, entirely rigid model receptors seem to
> underestimate the inhibitor constant, while using five flexible
> residues seems to overestimate the inhibitor constant.  I took an
> average of the free energy changes, this should be close to the values
> of Ki found when using two to three flexible residues.  The use of two
> to three flexible residues seems to give the best approximation of an
> affinity constant so far.  Does anyone agree?
>
>
>
> ------------------------------
>
> Message: 5
> Date: Thu, 09 Apr 2009 20:44:12 -0400
> From: mswingle at jaguar1.usouthal.edu
> Subject: Re: ADL: Urgent for my Ph.D. thesis and my career
> To: autodock at scripps.edu
> Message-ID: <fb513ee767be.49de5e1c at jaguar1.usouthal.edu>
> Content-Type: text/plain; charset=iso-8859-1
>
> Mostafa,
>
> It would be helpful if you could post more information from the dlg file.
> For example, what are the values of the different free energy components
> (electrostatic, internal energy etc.)? Do the structures of the docked
> complexes of these conformers look reasonable?
>
> Regards,
>
> Mark
>
> ----- Original Message -----
> From: Mostafa El-Miligy <melmiligy4m at yahoo.com>
> Date: Thursday, April 9, 2009 3:09 pm
> Subject: ADL: Urgent for my Ph.D. thesis and my career
> To: autodock at scripps.edu
>
>
> > Hi
> > ?
> > I used Autodock-4 for blind docking inside Trypanosoma Cruzi
> > Trypanothione Reductase (PDB 1AOG) and Telomerase reverse
> > transcriptase?(PDB 3DU6) enzymes and some of the docked compounds
> > showed estimated free energy of binding more than -70000000 Kcal/mole
> > for the first 4 ranked conformers so is it a logic or acceptable
> > calculation or not ? and if it is acceptable what is the explanation
> > of this very?low energy ?. However, the 5th conformer showed binding
> > energy in a normal range around -5 to -10 Kcal/mole.
> > Please reply to me as soon as possible because my Ph.D.?supervisor Dr
> > Aly Hazzaa said that Autodock-4 is a bad software and?not working
> > good. so please reply to me on this problem because it will affect?my
> > career badly.
> > ?
> > Thank you
> > ?
> > Yours,?
> >
> > Mostafa El-Miligy
> > ?
> >
> > Mostafa El-Miligy
> >
> > Ph.D. student
> > Department of Pharmaceutical Chemistry
> > Faculty of Pharmacy
> > University of Alexandria
> > Egypt
> >
> >
> >
> >
> > ________________________________________________
> > --- ADL: AutoDock List  --- http://autodock.scripps.edu/mailing_list ---
>
>
>
> ------------------------------
>
> Message: 6
> Date: Fri, 10 Apr 2009 10:15:15 +0800
> From: Liu Ji <zjuliuji at gmail.com>
> Subject: Re: ADL: Autodock4 error !!!
> To: autodock at scripps.edu
> Message-ID:
>        <b4830d230904091915q2d109723wc36e720c781e9000 at mail.gmail.com>
> Content-Type: text/plain; charset=ISO-8859-1
>
> Hi,
>
> Here's probably a wrong parameter name in your gpf files, maybe in you
> npts setting. The normal one is like
> "npts 40 40 40                        # num.grid points in xyz"
>  You are suggested to check it carefully.
> BTW, you'd better use the script "prepare_gpf4.py" to prepare you gpf
> files for virtual screening.
>
> On 4/9/09, raghu bhagavat <rag_vocal at yahoo.co.in> wrote:
> > Hi .........
> > In my VS program using Autodock4, i got an error like this while running
> the
> > autodock4 step............
> >
> > autogrid4: WARNING:? Unrecognized keyword in grid parameter file.
> >
> > autogrid4: ERROR:? You need to set the number of grid points using "npts"
> > before setting the ligand atom types, using "ligand_types".
> >
> > Unsuccessful completion
> >
> > how to proceed??
> >
> >
> >
> >       Add more friends to your messenger and enjoy! Go to
> > http://messenger.yahoo.com/invite/
> > ________________________________________________
> > --- ADL: AutoDock List  --- http://autodock.scripps.edu/mailing_list ---
> >
>
>
>
> ------------------------------
>
> Message: 7
> Date: Fri, 10 Apr 2009 10:39:38 +0100
> From: Gavin Seddon <home at gavsed.net>
> Subject: Re: ADL: Urgent for my Ph.D. thesis and my career
> To: autodock at scripps.edu
> Message-ID: <49DF13DA.3040401 at gavsed.net>
> Content-Type: text/plain; charset=iso-8859-1; format=flowed
>
> mswingle at jaguar1.usouthal.edu wrote:
> > Mostafa,
> >
> > It would be helpful if you could post more information from the dlg file.
> For example, what are the values of the different free energy components
> (electrostatic, internal energy etc.)? Do the structures of the docked
> complexes of these conformers look reasonable?
> >
> > Regards,
> >
> > Mark
> >
> > ----- Original Message -----
> > From: Mostafa El-Miligy <melmiligy4m at yahoo.com>
> > Date: Thursday, April 9, 2009 3:09 pm
> > Subject: ADL: Urgent for my Ph.D. thesis and my career
> > To: autodock at scripps.edu
> >
> >
> >
> >> Hi
> >>
> >> I used Autodock-4 for blind docking inside Trypanosoma Cruzi
> >> Trypanothione Reductase (PDB 1AOG) and Telomerase reverse
> >> transcriptase (PDB 3DU6) enzymes and some of the docked compounds
> >> showed estimated free energy of binding more than -70000000 Kcal/mole
> >> for the first 4 ranked conformers so is it a logic or acceptable
> >> calculation or not ? and if it is acceptable what is the explanation
> >> of this very low energy ?. However, the 5th conformer showed binding
> >> energy in a normal range around -5 to -10 Kcal/mole.
> >> Please reply to me as soon as possible because my Ph.D. supervisor Dr
> >> Aly Hazzaa said that Autodock-4 is a bad software and not working
> >> good. so please reply to me on this problem because it will affect my
> >> career badly.
> >>
> >> Thank you
> >>
> >> Yours,
> >>
> >> Mostafa El-Miligy
> >>
> >>
> >> Mostafa El-Miligy
> >>
> >> Ph.D. student
> >> Department of Pharmaceutical Chemistry
> >> Faculty of Pharmacy
> >> University of Alexandria
> >> Egypt
> >>
> >>
> >>
> >>
> >> ________________________________________________
> >> --- ADL: AutoDock List  --- http://autodock.scripps.edu/mailing_list---
> >>
> >
> > ________________________________________________
> > --- ADL: AutoDock List  --- http://autodock.scripps.edu/mailing_list ---
> >
> >
> Ok, these issues keep popping up on the list and I/WE are looking into
> reasons, it may be the ad4 algorithm and I would like to see it.  In the
> meantime one could argue -7x10e7 kj/mol would be
> -7e7 / e23
> ~-7e-16kj/molecule
> does this sound better?
> Or, if your supervisor keeps moaning tell him to stop and BUY GOLD from
> the guys in Cambridge but, this is still a genetic algorithm software!
> And I think it doesn't use Lamarkian like AD4 does!
>
>
>
> ------------------------------
>
> Message: 8
> Date: Fri, 10 Apr 2009 12:01:16 +0200
> From: "L. Michel Espinoza-Fonseca" <mef at ddt.biochem.umn.edu>
> Subject: Re: ADL: Urgent for my Ph.D. thesis and my career
> To: autodock at scripps.edu, melmiligy4m at yahoo.com
> Message-ID:
>        <d53635700904100301m16d19285w4b828aa7d7fb7704 at mail.gmail.com>
> Content-Type: text/plain; charset=ISO-8859-1
>
> Mostafa,
>
> I agree with Mark: you definitively need to share your dlg file with
> us so we can help you better. 'm pretty sure your problem has nothing
> to do with the algorithm, but with an incorrect setting-up of your
> protein or your ligand, which is producing an extremely favorable
> electrostatic interaction. You should take a look at the contribution
> of each term to the free energy of binding, this will give you a
> better hint on what's going on.
>
> Cheers,
> Michel
>
> On Fri, Apr 10, 2009 at 11:39 AM, Gavin Seddon <home at gavsed.net> wrote:
> > mswingle at jaguar1.usouthal.edu wrote:
> >>
> >> Mostafa,
> >> It would be helpful if you could post more information from the dlg
> file.
> >> For example, what are the values of the different free energy components
> >> (electrostatic, internal energy etc.)? Do the structures of the docked
> >> complexes of these conformers look reasonable?
> >> Regards,
> >>
> >> Mark
> >>
> >> ----- Original Message -----
> >> From: Mostafa El-Miligy <melmiligy4m at yahoo.com>
> >> Date: Thursday, April 9, 2009 3:09 pm
> >> Subject: ADL: Urgent for my Ph.D. thesis and my career
> >> To: autodock at scripps.edu
> >>
> >>
> >>
> >>>
> >>> Hi
> >>> ?I used Autodock-4 for blind docking inside Trypanosoma Cruzi
> >>> Trypanothione Reductase (PDB 1AOG) and Telomerase reverse transcriptase
> (PDB
> >>> 3DU6) enzymes and some of the docked compounds showed estimated free
> energy
> >>> of binding more than -70000000 Kcal/mole for the first 4 ranked
> conformers
> >>> so is it a logic or acceptable calculation or not ? and if it is
> acceptable
> >>> what is the explanation of this very low energy ?. However, the 5th
> >>> conformer showed binding energy in a normal range around -5 to -10
> >>> Kcal/mole.
> >>> Please reply to me as soon as possible because my Ph.D. supervisor Dr
> Aly
> >>> Hazzaa said that Autodock-4 is a bad software and not working good. so
> >>> please reply to me on this problem because it will affect my career
> badly.
> >>> ?Thank you
> >>> ?Yours,
> >>> Mostafa El-Miligy
> >>>
> >>> Mostafa El-Miligy
> >>>
> >>> Ph.D. student Department of Pharmaceutical Chemistry
> >>> Faculty of Pharmacy
> >>> University of Alexandria
> >>> Egypt
> >>>
> >>>
> >>>
> >>> ? ? ?________________________________________________
> >>> --- ADL: AutoDock List ?--- http://autodock.scripps.edu/mailing_list---
> >>>
> >>
> >> ________________________________________________
> >> --- ADL: AutoDock List ?--- http://autodock.scripps.edu/mailing_list---
> >>
> >>
> >
> > Ok, these issues keep popping up on the list and I/WE are looking into
> > reasons, it may be the ad4 algorithm and I would like to see it. ?In the
> > meantime one could argue -7x10e7 kj/mol would be
> > -7e7 / e23
> > ~-7e-16kj/molecule
> > does this sound better? Or, if your supervisor keeps moaning tell him to
> > stop and BUY GOLD from the guys in Cambridge but, this is still a genetic
> > algorithm software! ?And I think it doesn't use Lamarkian like AD4 does!
> >
> > ________________________________________________
> > --- ADL: AutoDock List ?--- http://autodock.scripps.edu/mailing_list ---
> >
>
>
>
> ------------------------------
>
> ________________________________________________
> --- ADL: AutoDock List  ---
> http://www.scripps.edu/pub/olson-web/doc/autodock/ ---
>
> End of autodock Digest, Vol 56, Issue 17
> ****************************************
>



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