From markm@portal.vpharm.com Thu Jun 17 20:57:45 1993 From: markm@portal.vpharm.com (Mark Murcko) Message-Id: <9306180557.AA12960@portal.vpharm.com> Subject: Rational Drug Design examples To: chemistry@ccl.net Date: Fri, 18 Jun 1993 01:57:45 -0500 (EDT) Along the same lines, the design of the carbonic anhydrase inhibitors involved a heavy dose of x-ray and modeling work; Trusopt is now in Phase III and with a little luck will get approved in 1994. See: Baldwin et al, J. Med. Chem., 1989, 32, 2510-2513 for a very brief intro. to the field. Jack Baldwin also spoke at the ACS Satellite Symposium on drug design held in March. Lots of recent examples of SBDD were given in our recent review in __Curr. Opinion in Struct. Biol.__ 1992, 2, 202-210. The Abbott C2 symmetric HIV protease inhibitors are another nice example. Last I heard, one of those compounds was still in the clinic. Finally, let's not forget the pioneering work of the Dupont group on the PLA2 inhibitors (Ripke, Blaney, et al, I don't have the reference in front of me, but most of you know which one I mean.) From rhn900@anusf.anu.edu.au Fri Jun 18 14:01:31 1993 From: Ross Nobes Message-Id: <199306180901.AA05045@anusf.anu.edu.au> Subject: re: g92 MULTIPLICITY=2 PROBLEM. To: GOVENDEM@che.und.ac.za Date: Fri, 18 Jun 93 19:01:31 EST GOVENDEM@che.und.ac.za writes: > I'm not very sure if this is a correct forum. I will pose the quetion > anyway. I tried frequency jobs with Nitric Oxide (multiplicity=2). > The theoretical value is 3915 wavenumbers, this is about twice > experimental one. PROBLEM 1 > This is not a problem with Gaussian 92, but rather a failing of UHF theory. For nitric oxide, the spin contamination in the UHF wavefunction increases rapidly as the bond is stretched. As a result, the UMP2 frequency (which I assume is being referred to above) is calculated to be ~3900 cm-1, compared with the experimental value of 1904 cm-1. See the paper by Frank Jensen (Chemical Physics Letters 169 (1990) 519) and the paper "Theory and Applications of Spin-Restricted Open-Shell Moller-Plesset Theory" by David Tozer et al. which is to appear shortly in Molecular Physics. -- * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * Ross Nobes * * Academic Consultant * * Supercomputer Facility Phone: + 61 6 249 4154 / 4161 * * Australian National University Fax: + 61 6 247 3425 * * Canberra, ACT 0200 * * Australia E-mail: R.Nobes@anu.edu.au * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * From martin@biochem.kth.se Fri Jun 18 04:51:10 1993 Message-Id: <9306180945.AA09471@kiev.physchem.kth.se> Date: Fri, 18 Jun 1993 03:51:10 +0100 To: chemistry@ccl.net From: martin@biochem.kth.se (martin) Subject: GRID, drug-design and mol.mod. Dear readers, In the light of the discussion about usefulness of molecular modelling and comments about the GRID program by Bob Carter I want to tell a little story: One of the main actors in the following true story is the GRID program nicely described by Bob Carter in a recent message to the net. I arranged a workshop in molecular modelling during an EMBO course last week. Most of the participants where experimental molecular biologists and they had never worked with comp. chem. methods before. Therefore I worried a little bit..... In the morning I read the paper in Nature 3rd of june by Mark von Itzstein et al about drugs against influenza virus. They used the GRID program to model strong inhibitors for a target enzyme. I thought that this would be a very nice system to model in the workshop. Luckily the coordinates for the target enzyme was available at the Brookhaven database, so I transfered the structure by ftp to my workstation and displayed it by the Sybyl program. The active site was then centered in a box of 16,16,16 A. Then I repeated the GRID calculations that was reported in the Nature paper. Their results were reproduced very nicely. Then it was easy to model in their newly designed inhibitors according to the GRID maps and the structures displayed in the paper. The most striking thing was that all this was done within one hour. I then modified parts of the workshop to include these studies as well and I think that the participants appreciated this part mostly because they could follow and look at the results of the calculations interactively. What I appreciate mostly from this is that the modelling work was easily reproduced and easy to interpret. Many molecular modelling papers of today lacks these conditions due to reasons like: 1) The paper is written in a way that only an experienced scientist in the same field really understands it. 2) The coordinates of the target protein is not available or put on hold in the Brookhaven Databank. 3) The computer programs used are not available or is written in some very fancy C-language which cannot compile on the home computer. I think we all have to improve on making molecular modelling and computational chemistry more easily available to the rest of the scientific community. I'm an optimist and think I already see lots of steps taken in that direction. Greetings and have a nice summer, Martin Norin Dept. Biochem. KTH Stockholm From TSHEHLA@che.und.ac.za Tue Jun 18 14:45:44 1993 Message-Id: To: Chemistry@ccl.net From: TSHEHLA@che.und.ac.za Date: 18 Jun 93 12:45:44 +0200 (SAST) Subject: Energy Decomposition K-M package Hello out there; I highly appreciate the responses for NO problem. To all of you I would like to say "THANK YOU INDEED." Our world becomes really ours. I have yet another problem. Is any one out there, aware of email for professor Morokuma K ? I ran through gopher for such details, but I only got his Fax, which to my dissapointment does not work. He is in the "INSTITUTE FOR MOLECULAR SCIENCE 444, OKAZAKI JAPAN". Or does any have information regarding "energy decomposition package by MOROKUMA?" Thanks in advance. TM Tshehla From BOYD_DONALD_B@Lilly.com Tue Jun 18 02:52:14 1993 Date: 18 Jun 1993 07:52:14 -0500 (EST) From: "DONALD B. BOYD" Subject: successful examples of CADD To: chemistry@ccl.net Message-Id: <01GZIL5A659U8WXKF9@INET.D48.LILLY.COM> There are many examples of computer-aided molecular design and structure-based molecular design. Besides the examples posted yesterday and today, Yvonne Martin, Mark Bures, and Peter Willett presented a nice success in Chapter 6 of "Reviews in Computational Chemistry", Vol. 1, K.B. Lipkowitz and D.B. Boyd, VCH, New York, 1990. Four other examples are given in Chapter 10 of that book. Practically any recent issue of Journal of Medicinal Chemistry has further examples. From: BOYD DONALD B (MCVAX0::QSAR) To: VMS MAIL ADDRESSEE (INT::"chemistry@ccl.net") cc: BOYD DONALD B (MCVAX0::QSAR) From cqsimpson@halnet.com Fri Jun 18 04:21:15 1993 Date: Fri, 18 Jun 1993 09:21:15 -0500 From: cqsimpson@halnet.com (Charlie Simpson) Message-Id: <9306181421.AA24502@cre2> To: chemistry@ccl.net Subject: Transferring rs6k graphics to PCs Howdy Netters! Here at Halliburton Services research center, we use MSI's AVS ChemistryViewer and QUANTA to view output from various calculations on rs6k. We would like to be able to transfer the graphics to our PCs for use in presentations. Is there any software available for rs6k to capture graphics and save it to a particular format, such as tif or encapsulated postscript, so that it may be imported by a presentation program on a PC? AVS has an option to save a view as a .ps file, however, our presentation programs can't read this format. Overall, all of the presentation programs seem to be able to import .tif files. So, is there any way to go from .ps on an rs6k to .tif on a PC? I'll keep a list of all the responses and broadcast them back. Thanks in andvanced. Regards, ================================================================================ Charlie Simpson Ph.D. cqsimpson@halnet.com Halliburton Services P.O. Box 1431 Phone 405/251-4564 Duncan, OK 73536-0444 Fax 405/251-3218 Life for him was an adventure, and perilous indeed, but men were not made for safe havens. -- Edith Hamilton on Aeschylus ================================================================================ From siroiss@CERCA.UMontreal.CA Fri Jun 18 06:53:08 1993 From: siroiss@cerca.umontreal.ca (Suzane Sirois) Message-Id: <9306181553.AA04986@pellan.CERCA.UMontreal.CA> Subject: Re:Drug Design To: CHEMISTRY@ccl.net Date: Fri, 18 Jun 1993 11:53:08 -0500 (EDT) following the question concerning successfull candidates from a rational drug design view : there is two main ways to design drugs rationnally: 1) from the structure of a LEAD compound or a substrate (peptidomimetic compounds,the main problem is the short half-lives and poor bioavailability and the conversion of a peptide-based inhibitor into an orally active compound is an important challenge for the field of synthetic chemistry) 2) and/or from the knowledge of the active site of the target enzyme and the substrat or a natural effector. In the second case the model of the lock and key is exploited with conjonction of the hydrogen bondings, the intermolecular forces, etc. for the second case thereis some references i) Structure-Based Strategies For Drug Design and Discovery, I.D.Kuntz, Science vol.257 21 august 1992 ii) Compounds in the clinical trial : 1)K.Appelt et al. J.Med.Chem., 34, 1925 (1991) 2)M.D. Varney et al., ibid., 35, 663 (1992) ************************************************* * Suzanne Sirois * * Office CERCA * * Theoretical Chemistry Groups * * Departement de Chimie * * Universite de Montreal * * P.O. 6128, Succ. A * * Montreal, Quebec H3C 3J7 * * Canada * * * * tel: (514) 369-5228 * * e-mail: siroiss@chimcn.umontreal.ca * * fax: (514) 343-7586 * ************************************************* From system@alchemy.chem.utoronto.ca Fri Jun 18 09:05:50 1993 Date: Fri, 18 Jun 93 13:05:50 -0400 From: system@alchemy.chem.utoronto.ca (System Admin (Mike Peterson)) Message-Id: <9306181705.AA27120@alchemy.chem.utoronto.ca> To: Chemistry@ccl.net Subject: Re: Energy Decomposition K-M package Hasn't Morokuma left IMS to go somewhere in the US? The Energy Decomposition has been implemented in MONSTERGAUSS by Ray Poirier and myself; the program is no longer being developed, and is based on obsolete algorithms (no direct SCF, etc), but runs on almost any system including UNIX workstations. It has been donated to the Gaussian developers, but I have no idea if it will be incorporated in a future version. It will also do a counterpoise correction for either regular SCF or the Energy Decomposition, if you believe it is useful. Mike. (please send e-mail re MONSTERGAUSS to mgauss@alchemy.chem.utoronto.ca) From carlos@pap.chem.uic.edu Fri Jun 18 07:33:05 1993 Date: Fri, 18 Jun 93 12:33:05 CDT From: Carlos Simmerling Message-Id: <9306181733.AA08700@pap.chem.uic.edu> To: chemistry@ccl.net Subject: New MOIL version released RE-RELEASE OF A PUBLIC DOMAIN MOLECULAR DYNAMICS PROGRAM We are announcing a new release of moil - moil.006 . moil is a public domain molecular dynamics program that is available via anonymous ftp. At the end of the file we attached instructions of how to get the code. The code was developed by Ron Elber, Adrian Roitberg, Carlos Simmerling Haiying Li, Gennady Verkhivker and Robert Goldstein, Other contributers that helped in testing, developing parameter sets and writing documentation: Danuta Rojewska, Chyung Choi and Alex Ulitsky. Compare to previous releases (003 and 004) the present code has a number of bug fixes and new features. The most major addition is the visualization program for Silicon Graphics (moil-view , author: Carlos Simmerling). Other features include considerable speed up of most intensive computations (up to a factor of 3) and undoubtedly a number of unknown bugs. Please note that old connectivity files will not run on 006 and it is necessary to regenerate them. At present existing modules are: con : creating connectivity files con.specl: creating special connectivity files for curve crossing calculations (H. Li, R. Elber and J. Straub, JBC in press) con.specl1: need also to run con.specl1 to get the curve crossing to work. energy : good old vanilla energy calculation dyna : good old vanilla dynamics using velocity Verlet with RATTLE ( (velocity SHAKE), also possible to use periodic (cubic) boundary conditions and also possible to use LES (Locally Enhanced Sampling Protocol) (For current implementation see A. Roitberg and R. Elber, J.Chem.Phys 95,9277(1991) and references therein) We worked on optimizing the dynamics code, The previous version of RATTLE was improved and the use of double cutoffs (for van der Waals and electrostatic) also speeds-up things. While more can be undoubtedly done, at present we are doing better than anyone else we are compared to. chain or chmin: Reaction path algorithms that are based on optimization of the complete path. (R. Czerminski and R. Elber IJQC 24,167(1990)) ccrd : Converting CooRDinates between different formats boat : provide values of BOnds Angles and Torsions. I.e. internal coordinates for a set of structrues. rms_resd : rms calculations for those who care fluc : fluctuations for those who are not at a minimum (from MD) umbr : Umbrella sampling calculations. (G. Verkhivker, R. Elber and Q.H. Gibson JACS 114,7866(1992)) freee : free enrgy calculations along reaction paths by perturbation or thermodynamic intergration (R. Elber, JCP 93,4312(1990)) mini_tn : minimization using truncated Newton Raphson (public domain code of Stephen G. Nash) mini_pwl : Conjugate gradient algorithm for energy minimization. puth : add hydrogens to protein data bank coordinates to obtain acceptable MOIL coordinates for energy calculations. Done according to geometric criteria (no fancy stuff) therm : free energy calculations where the potential parameters are changing. Alchemistry. For LES implememntation see: (G. Verkhivker, R. Elber and W. Nowak JCP 97,7838(1992)) contacts : analyzing dynamics to find collisions between specific residues rgyr : calculate radius of gyration torstat : compact torsion statistics (as compared to boat), give phi.psi.chi1 values for all residues mult : multiply coordinates of desired residues for LES calculations. AND FINALLY: moil-view : (creator - Carlos Simmerling) A visualization program (not modeling!) for Silicon Graphics (only). Easy to use and well interfaced with the features of moil. Dynamics of shaded spheres, sticks or mixtures. Easy recording to video tapes. Note that this program does NOT require the use of moil but can also use other file formats such as PDB. The code is in the public domain. We are giving up any right to the code. You may include it in your own code and distribute it further. You may transfer it "as is" to other users without asking us for permission. However, we request that this message will be kept. In case that changes are made to the code we request that a list of changes will be provided to the new users. We shall not be responsible for other people's bugs, we can hardly handle our own. The code is given with the friendly understanding that you will not try to use this code as part of a commercial software package. However, we put no restrictions on other type of products that may emerge using this code. Reference should be made to the authors of the programs as listed in the makefile to the extent that this program helps/distracts you in your work. Contact Ron Elber (ron@pap.chem.uic.edu) for proper references. BUGS/PROBLEMS OR OTHER TYPES OF DISCOMFORT ASSOCIATED WITH MOIL CAN BE REPORTED TO: ron@pap.chem.uic.edu We shall make significant effort to answer inquiries and especially to fix bugs. Note however (as is quite clear from the price tag on this package) that we are not making our living selling this code. Therefore we do not promise to provide satisfactory answers to all questions. On what is free there is no guarantee! TO GET THE CODE: ftp 128.248.186.70 user-name:anonymous passwd: your e-mail cd dist get moil.006.tar.Z (source code only) get moil.dat.tar.Z (documentation and parameters/property and monomer files in the documentation you made find useful the file tutorial) get moil.test.tar.Z (test files - input and output - quite large and may be a real pain to ftp, useful also as a starting point to construct your own input). get view.tar.Z the moil-view visualization program of Carlos Simmerling quit On your machine uncompress moil.006.tar.Z tar xvf moil.006.tar repeat the same procedure for the other files. cd moil.src.006 edit the makefile and change the variables FC and FFLAGS to fit your machine. then type "make" and you should be all set. A good place to start is the tutorial in moil.doc, please note however that some of the docu were prepared with the old versions, so things may have slightly different output than you expect. Old input should work. To compile moil-view go to the view.source directory and type make. The machine MUST be a Silicon Graphics. Look at the file view.doc to get started. From DSMITH@uoft02.utoledo.edu Fri Jun 18 09:54:07 1993 Date: Fri, 18 Jun 1993 14:54:07 -0500 (EST) From: "DR. DOUGLAS A. SMITH, UNIVERSITY OF TOLEDO" Subject: no anon. ftp at UToledo - temporarily To: chemistry@ccl.net, mmodinfo@uoft02.utoledo.edu Message-Id: <01GZJ06LITB0000VWK@UOFT02.UTOLEDO.EDU> A software upgrade has temporarily disabled anonymous ftp at the University of Toledo, where I have placed several files of interest. There will be an announcement on the mail exploder when it is again available (we hope next Tuesday). Sorry for the inconvenience. Doug Douglas A. Smith Assistant Professor of Chemistry The University of Toledo Toledo, OH 43606-3390 voice 419-537-2116 fax 419-537-4033 email dsmith@uoft02.utoledo.edu