From owner-chemistry@ccl.net Thu Jun 17 03:17:00 2010 From: "Kalju Kahn kalju.:.chem.ucsb.edu" To: CCL Subject: CCL: Docking Software for Macrocycles Message-Id: <-42128-100617031548-899-RfXnB0r2drVyhZfpbeaQWA . server.ccl.net> X-Original-From: "Kalju Kahn" Content-Transfer-Encoding: 8bit Content-Type: text/plain;charset=iso-8859-1 Date: Thu, 17 Jun 2010 00:14:49 -0700 MIME-Version: 1.0 Sent to CCL by: "Kalju Kahn" [kalju!=!chem.ucsb.edu] John, Could you turn the order around: do a conformational analysis of the scaffold (with possible restraints dictated by the shape of the binding pocket), then create a virtual library of compounds by substituting into the macrocycle using a set of low-energy conformers. I think Helgi Adalsteinsson (Bioorganic & Medicinal Chemistry 8 (2000) 625-635) tried something like this. He also wrote some scripts to automate this process. Hope this helps, Kalju > > Sent to CCL by: "John Furr" [john.furr|gmail.com] > Hey gang, > > I'm looking for advise/tips about docking software that will work well > with large macrocycles...19+ ring atoms. Software can be commercial or > not. > > Currently we are using the Schrodinger suite of tools with moderate > success. However our biggest limitation is that glide does not sample > large ring conformations. This means that for every compounds we want to > dock we have to first do an upfront conformational analysis and this takes > several hours to do in a complete manner. > > To put it in units of time. It takes me about 4 hours per compound to get > a docked pose for a single CPU. There are literally times that the > chemistry team is faster than me! > > Obviously we are very interested in exploring other options that would > allow us to improve our throughput without compromising robustness. > > So gang any advise and or tips? > > Cheers > John Furr> > > ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Dr. Kalju Kahn Department of Chemistry and Biochemistry UC Santa Barbara, CA 93106 From owner-chemistry@ccl.net Thu Jun 17 08:30:00 2010 From: "Vincent Leroux vincent.leroux:loria.fr" To: CCL Subject: CCL: Entropy in docking Message-Id: <-42129-100616214953-2010-giQin7GEz65XNRzxVM89Pg===server.ccl.net> X-Original-From: Vincent Leroux Content-Transfer-Encoding: 8bit Content-Type: text/plain; charset=ISO-8859-1 Date: Thu, 17 Jun 2010 02:52:48 +0200 MIME-Version: 1.0 Sent to CCL by: Vincent Leroux [vincent.leroux]~[loria.fr] Hi Nikolay, Most docking programs scoring functions so simplistic that they are not on the same level of theory as anything dealing with entropy... So during the docking process, entropy is not explicitly taken into account. A typical scoring function will have at least three terms: - one accounting for the "direct" protein-ligand interactions (electrostatics, hydrogen bonds...) - an internal ligand penalty for avoiding unrealistic conformations - the 3rd term, even more empirically parameterized than the two others, is related to the "desolvation effect". If docking scoring functions could be considered as rigorous measures of the free energy of binding, the entropy would be located in the latter. With such simple scoring functions, it is being assumed that a ligand "filling space" on a protein receptor "liberates" the waters that were there* from an entropically-restricted* state, releasing them into a more favorable* "bulk solvent" state, the most "hydrophobic" the active site surface and the ligand shape fitting it the better* the energetic gain, and that this dominates* the entropic contribution in the whole ligand binding process (* indicating assumptions that can be heavily challenged). You might use docking to get a set (1-10, not hundreds) of acceptable starting conformations before more complex simulations that will possibly account for entropy. Some of such post-docking optimizations might be included and automated in the docking program itself (Glide being the most well-known example here). In any case, the docking scoring function is dumped, usually for a forcefield-based potential. For estimating entropy rigorously extensive sampling is required, preferably with the protein-ligand system modeled in explicit water. Regards VL Le 16/06/10 19:11, Nikolay Novikov nikolay_novikov%%yahoo.com a écrit : > Sent to CCL by: "Nikolay Novikov" [nikolay_novikov : yahoo.com] > Dear CCL members, > > Would you advice me on how to account for entropy in protein-ligand docking? What software is used to account for entropy when docking yields several hundreds of docked positions? > Thank you all! > > Sincerely, > Nikolay Novikov > Ph.D. student,Lviv University, > Ukraine> > > From owner-chemistry@ccl.net Thu Jun 17 13:14:00 2010 From: "John john{:}ccdc.cam.ac.uk" To: CCL Subject: CCL: Docking Software for Macrocycles Message-Id: <-42130-100617081934-2117-IY0NyV7+o80CQH+/S8gyow[-]server.ccl.net> X-Original-From: "John" Content-Language: en-gb Content-Transfer-Encoding: 7bit Content-Type: text/plain; charset="us-ascii" Date: Thu, 17 Jun 2010 09:58:23 +0100 MIME-Version: 1.0 Sent to CCL by: "John" [john{:}ccdc.cam.ac.uk] Dear John, GOLD can handle macrocycle docking but you will need to calculate a ring template library for each macrocycle type you are studying. This will save you time if you are studying many analogues of one particular macrocycle as you will only need to do the conformational analysis once to generate the appropriate ring template library. Please contact admin++ccdc.cam.ac.uk for details on how to obtain GOLD Regards John -----Original Message----- > From: owner-chemistry+ccdc-announce==ccdc.cam.ac.uk++ccl.net [mailto:owner-chemistry+ccdc-announce==ccdc.cam.ac.uk++ccl.net] On Behalf Of John Furr john.furr/./gmail.com Sent: 16 June 2010 15:21 To: Rutland, Anne Subject: CCL: Docking Software for Macrocycles Sent to CCL by: "John Furr" [john.furr|gmail.com] Hey gang, I'm looking for advise/tips about docking software that will work well with large macrocycles...19+ ring atoms. Software can be commercial or not. Currently we are using the Schrodinger suite of tools with moderate success. However our biggest limitation is that glide does not sample large ring conformations. This means that for every compounds we want to dock we have to first do an upfront conformational analysis and this takes several hours to do in a complete manner. To put it in units of time. It takes me about 4 hours per compound to get a docked pose for a single CPU. There are literally times that the chemistry team is faster than me! Obviously we are very interested in exploring other options that would allow us to improve our throughput without compromising robustness. So gang any advise and or tips? Cheers John Furrhttp://www.ccl.net/cgi-bin/ccl/send_ccl_messagehttp://www.ccl.net/chemistry/sub_unsub.shtmlhttp://www.ccl.net/spammers.txtLEGAL NOTICE Unless expressly stated otherwise, information contained in this message is confidential. If this message is not intended for you, please inform postmaster++ccdc.cam.ac.uk and delete the message. The Cambridge Crystallographic Data Centre is a company Limited by Guarantee and a Registered Charity. Registered in England No. 2155347 Registered Charity No. 800579 Registered office 12 Union Road, Cambridge CB2 1EZ. From owner-chemistry@ccl.net Thu Jun 17 16:11:00 2010 From: "domenico quartarolo quartarolo[*]unical.it" To: CCL Subject: CCL: TDDFT and B2PLYP Message-Id: <-42131-100617100308-8962-rOxrzsTLA1ASJJBsICDXwA[A]server.ccl.net> X-Original-From: "domenico quartarolo" Date: Thu, 17 Jun 2010 10:02:26 -0400 Sent to CCL by: "domenico quartarolo" [quartarolo*unical.it] I'm using b2plyp for excitation energies calculation as implemented in orca software. For my system the cis(d) correction to b2lyp is of -0.3 eV and the initial excited state excitation energy (b2lyp within Tamm-Dancoff approximation) is 2.4 eV. This last value is greater by about 0.2 eV with respect to the full TD treatment, so the overall effect is that the final excitation energy (with cis(d) correction) does not improve against, say, b3lyp tddft calculation. I would like to know if there is a way to solve this problem with available quantum chemistry packages. best regards domenico quartarolo:-:unical.it From owner-chemistry@ccl.net Thu Jun 17 17:48:00 2010 From: "Alfredo Tlahuice tlahuicef * fisica.unam.mx" To: CCL Subject: CCL: About Symmol program use Message-Id: <-42132-100617113939-26088-hUf/xn1d7Drf0aZ6EbEGzA---server.ccl.net> X-Original-From: "Alfredo Tlahuice" Date: Thu, 17 Jun 2010 11:38:47 -0400 Sent to CCL by: "Alfredo Tlahuice" [tlahuicef*fisica.unam.mx] Hi there Does anybody have the symmol program? I need to change the puntual group of a molecule from Ih to Th. Any advice? Alfredo Tlahuice From owner-chemistry@ccl.net Thu Jun 17 18:25:00 2010 From: "Josh Szekely j-szekely.]_[.onu.edu" To: CCL Subject: CCL: Qchem aborting unexpectedly Message-Id: <-42133-100617145647-17087-WHMdOwdiAMMuaDJQp+4Mzg]_[server.ccl.net> X-Original-From: "Josh Szekely" Date: Thu, 17 Jun 2010 14:55:53 -0400 Sent to CCL by: "Josh Szekely" [j-szekely,onu.edu] I am trying to run optimization and frequency calculations on qchem using the SS(V)PE solvation model with DFT theory. The initial SCF cycle for all of my calculations finishes for the gas phase, but when the solvation method is applied, the calculation aborts without any sort of error message. I've tried adjusting memory settings and a few other parameters, but the same thing always happens. Does anyone have any idea as to what may be causing this issue? Josh Szekely j-szekely:-:onu.edu From owner-chemistry@ccl.net Thu Jun 17 22:06:01 2010 From: "Eric Bennett ericb=-=pobox.com" To: CCL Subject: CCL: Docking Software for Macrocycles Message-Id: <-42134-100616220742-1425-N3Dax4AJsR7HANpgTvg1Bw*_*server.ccl.net> X-Original-From: Eric Bennett Content-type: text/plain; charset=us-ascii; format=flowed Date: Wed, 16 Jun 2010 21:07:06 -0400 MIME-version: 1.0 Sent to CCL by: Eric Bennett [ericb.:.pobox.com] Since you are already using Glide... If you are making many analogs of macrocycles often sharing similar cores, the new version of the Schrodinger suite just released a couple weeks ago has improved support for user-input ring template data, so once you carry out the time-consuming up front step of determining the low energy conformations for your core ring structures subsequent searches should be much faster. There is a utility to help automate the ring templating process, and it is described in section 17.8 of the macromodel manual since the actual template generation is done with macromodel. I am not sure of all the settings it uses (ie, does it use LMCS which is probably a good idea in your case) but the default 20,000 search steps might be too small. >Sent to CCL by: "John Furr" [john.furr|gmail.com] >Hey gang, > >I'm looking for advise/tips about docking software that will work >well with large macrocycles...19+ ring atoms. Software can be >commercial or not. > >Currently we are using the Schrodinger suite of tools with moderate >success. However our biggest limitation is that glide does not >sample large ring conformations. This means that for every >compounds we want to dock we have to first do an upfront >conformational analysis and this takes several hours to do in a >complete manner. > >To put it in units of time. It takes me about 4 hours per compound >to get a docked pose for a single CPU. There are literally times >that the chemistry team is faster than me! > >Obviously we are very interested in exploring other options that >would allow us to improve our throughput without compromising >robustness. > >So gang any advise and or tips? > >Cheers >John Furr -- Eric Bennett, ericb(-)pobox.com We used to quip that "password" is the most common password. Now it's "password1." Who said users haven't learned anything about security? -Bruce Schneier