From chemistry-request@server.ccl.net Wed Dec 30 11:26:38 1998 Received: from www.ccl.net (www.ccl.net [192.148.249.5]) by server.ccl.net (8.8.7/8.8.7) with ESMTP id LAA15341 for ; Wed, 30 Dec 1998 11:26:37 -0500 Received: from bioc1.msi.com (bioc1.msi.com [146.202.0.2]) by www.ccl.net (8.8.3/8.8.6/OSC/CCL 1.0) with SMTP id LAA18444 Wed, 30 Dec 1998 11:20:18 -0500 (EST) Received: by bioc1.msi.com (931110.SGI/930416.SGI) for chemistry@www.ccl.net id AA14604; Wed, 30 Dec 98 08:19:03 -0800 Message-Id: <9812301619.AA14604@bioc1.msi.com> Received: from osman-pc.msi.com(146.202.7.202) by bioc1.msi.com via smap (V2.0) id xma014594; Wed, 30 Dec 98 08:18:40 -0800 X-Sender: osman@146.202.6.217 (Unverified) X-Mailer: QUALCOMM Windows Eudora Pro Version 4.0.1 Date: Wed, 30 Dec 1998 08:20:58 -0800 To: chemistry@www.ccl.net, CHMINF-L@LISTSERV.INDIANA.EDU From: "Osman F. Guner" Subject: Abstracts of papers at ACS - Pharmacophore Symposium Cc: owner-qsar_society@unil.ch Mime-Version: 1.0 Content-Type: text/plain; charset="iso-8859-1" Content-Transfer-Encoding: 8bit X-MIME-Autoconverted: from quoted-printable to 8bit by server.ccl.net id LAA15342 TUESDAY AFTERNOON Section A Techniques in Pharmacophore Development 1 O. Güner, Organizer, Presiding 1:30*45. What makes a good pharmacophore? E. Abrahamian, S. L. Chan, R. D. Clark, T. W. Heritage An experienced molecular modeler can often look at a particular pharmacophore-based query and know whether it is likely to produce useful results when used to carry out a 3D search - i.e., whether it will be so general that it "hits" too many structures, or so specific that it "hits" too few. The recent introduction of partial match capabilities in commercial 3D searching packages has rendered such evaluation considerably more difficult, but it is still humanly possible. In carrying out recent work on automated pharmacophore hypothesis generation, it became clear that a priori evaluation of the information content and/or discrimination power of a 3D query is in fact quite a complex task. Nonetheless, certain general relationships do exist between query structure and information content which can allow quantitative analysis which goes beyond simple rules of thumb. Results of such analyses will be presented. 2:00*46. Automatic pharmacophore generation using catalyst. J. Sutter, O. Güner, R. Hoffman, H. Li, M. Waldman Catalyst is a program suite that automatically generates pharmacophores using only experimentally-obtainable ligand information; 2D structure and biological activity. Catalyst calculates a conformational model for each molecule, creates initial pharmacophores that are common among the active compounds but not among the inactive compounds, and optimizes the pharmacophores using simulated annealing. Each pharmacophore is scored using a cost function that accounts for its complexity, the deviation from ideal chemical weights for each chemical feature, and the differences between the predicted and measured activities. The pharmacophores can be used to predict the activity of unknown compounds or to search for new possible leads contained in 3D chemical databases. In this presentation, validation studies involving new developments in Catalyst including the use of variable weights and tolerances will be discussed. 2:30*47. Evaluation of automated methods for pharmacophore model generation. K. Gundertofte, B. Bjørnholm, M. Langgård A pharmacophore model of the serotonin reuptake site has been developed using classical pharmacophore modelling tools.1 The model can explain enantioselectivity as well as selectivity towards norepinephrine and has been validated against several test compounds. Newer, automated techniques for pharmacophore model generation, Catalyst, Cerius2 and Flo96 have been applied on the serotonin reuptake site. The generated pharmacophore models have been compared to our classical model. Differences in performance of the applied methods will be discussed. Reference1: Gundertofte, K., Bøgesø, K.P. and Liljefors, T., A Stereoselective Pharmacophoric Model of the Serotonin Reuptake Site. In H. van de Waterbeemd, B. Testra and G. Folkers (Eds.), Computer-Assisted Lead Finding and Optimization. WILEY-VCH, Weinheim, 1997, pp. 443-459. 3:00*48. Substrate mapping through a multiple copy simultaneous search : a new methodology applied to peptide deformylase. L. Patiny The multiple copy simultaneous search method (MCSS) was developed by Karplus in order to create functionality maps of binding sites for proteins having a known catalytic site. In this communication we would like to present the use of the MCSS in order to quickly determine the position of a catalytic site knowing a substrate and the structure of the protein. In order to reach this goal we are using directly the substrate in the minimisation. To circumvent the difficulties linked to the degree of freedom, the substrate is reduced, in a first step, to 50%. After the MCSS, we let the substrate inflate in the protein. We will present results that was obtained on peptide deformylase and compare them to experimental results. 3:30*49. Exploiting pharmacophores using oracle. K. Davies, R. Ponstance The 3D pharmacophore searching technology developed by Chemical Design in the early 1990s was adapted to provide a quantitative measure of pharmacophore diversity for Combinatorial Chemistry Library Design. This used the concepts of pharmacophore fingerprints or keys which have also been used to identify pharmacophores which may be associated with activity. Recent advances in computer speed and the falling costs of diskspace, have allowed the pharmacophores for individual molecules to be stored in an ORACLE database. This enables much more rapid development and testing of hypothesis for the pharmacophore responsible for a given activity which in turn may significantly reduce the time taken for lead explosion and lead optimisation. This paper includes examples using this technology to select molecules to exhibit a desired selectivity of biological response. WEDNESDAY MORNING Section A Techniques in Pharmacophore Development 2 NEW ALGORITHMS IN PHARMACOPHORE DEVELOPMENT O. Güner, Organizer, Presiding 8:30*57. Field-based similarity forcing: a conformationally-flexible approach to pharmacophore perception. J. R. Blinn, G. M. Maggiora, D. C. Rohrer A new molecular field-based similarity forcing method for matching conformationally flexible molecules is presented. The method extends earlier work on field-based similarity matching of molecules based upon the MIMIC program, by directly coupling the similarity matching function to a molecular mechanics force-field. Thus conformational energetics are now fully accounted for within the similarity-matching process, and conformational searching constrained by the similarity function ('similarity forcing') can be carried out concurrently. This method is quite similar to that used in NMR-based structure determination with NOE distance constraints. Although a Monte Carlo search procedure is used in the present work, any type of search procedure can be employed. After the best matchings have been determined, a series of post matching analyses are performed to obtain information on the underlying pharmacophoric patterns. These analyses included an evaluation of appropriate similarity fields and inter-molecular atom-atom similarities. An example from several HIV-1 RT inhibitors will be presented to illustrate the salient features of the method. 9:00*58. Extraction of the maximum 3d common substructure from a set of ligands. J. Gasteiger, S. Handschuh, M. Wagener Ligands binding to the same receptor are superimposed in order to extract the essential three-dimensional structure necessary for ligand binding. In this process, geometry changes due to conformational flexibility are explored to maximize overlap. The entire process uses a combination of a genetic algorithm with a quasi-Newton optimizer. The method can be applied to a set of ligands even if the 3D structure of the receptor is not known, and to hits from high-throughput screening. 9:30*59. Vector and tensor pharmacophores from quantum mechanical calculations. T. Clark, M. Hennemann, B. Martin The detailed electrostatic and polarizability information available from even very simple (in this case AM1 semiempirical MO) quantum mechanical calculations can be converted into hydrogen bonding vectors, linear quadrupoles for aromatic ring binding sites and group polarizability tensors to characterize lipophilic groups. The spatial relationships between the different sorts of binding site on the molecule can be used to derive 3D-pharmacophores both from limited (20-50 compound) activity data and from larger numbers of compounds that have been identified to be active. The pharmacophore models thus derived can be used to scan entire 3D-databases at a speed of about 2,500 molecules per processor minute to obtain quantitative estimates of individual activities. Examples of the results of such searches will be presented. 10:00*60. The concept of pharmacophore and anti-pharmacophore shielding in drug design and structure-property relationships. I. B. Bersuker, S. Bahceci, J. E. Boggs, R. S. Pearlman The widely employed concept of Pharmacophore (Pha) is complemented by the notions of Basic Skeleton (BS) and Anti-Pharmacophore Shielding (APS). The Pha is assumed to be the necessary element that produces the activity under consideration, while the BS is formed by adding to the Pha maximum possible atomic groups that do not influence the activity (they fill the cavities in the ligand-receptor interaction), and the APS is defined as additional (to the BS) groups that hinder the proper Pha-receptor docking, thereby diminishing (partially or completely) the activity. In combination with our Electron-Conformational method of pharmacophore identification, suggested earlier, the concept of BS and APS simplifies the search for Pha and allows for approximate numerical predictions of activities. These computer implemented novel ideas are applied to two problems: rice blast activity and angiotensin-converting enzyme inhibitors. 10:30*61. Advanced pharmacophore keys. S. J. Cato Chem-X software allows study of the potential pharmacophores exhibited by a collection of molecules and expresses the results as pharmacophoric fingerprint, called a pharmacophore key. It recognizes up to seven types of interaction centers automatically and finds all possible permutations of three of these as potential pharmacophores in each low energy conformation, setting the appropriate bits in the key. This paper compares and contrasts two extensions to the standard pharmacophore keys. The use of four-center pharmacophores (rather than three), allows the pharmacophores found to be space filling (rather than planar) and creates a much larger potential pharmacophore space. Alternatively, 'profiling', allows a count of the pharmacophores (as opposed to single bits of each) to be stored in the key on either a molecular or conformational counting basis. The application to the diversity comparison of libraries and diverse subset selection is examined. WEDNESDAY AFTERNOON Section A Techniques in Pharmacophore Development 3 New Approaches: PHARMACOPHORES FROM RECEPTOR ACTIVE SITES O. Güner, Organizer, Presiding 1:30*62. Genefold: protein sequence to structure to receptor pharmacophore. A. Nayeem When a given protein sequence does not exhibit sufficient sequence identity to known proteins, threading methods have often proven successful in identifying protein folds most likely to be compatible with that sequence. Here we examine how far we can go beyond fold recognition. The application GeneFold, a threading program developed by Godzik and Skolnick at Scripps, for developing a pharmacophore model for the binding site of an enzyme is shown. The value of the model as a basis for searching chemical libraries is also discussed. 2:00*63. Novel structure based approaches to pharmacophore model generation and library focusing. C. M. Venkatachalam, P. Kirchoff, J. Jiang, M. Waldman Given a library of compounds, the problem of identifying compounds that can satisfactorily dock and interact with a known Protein active site, is a challenging one. To be able to select potentially interesting compounds from a library using known information about the three dimensional structure of the active site is very crucial in generating leads especially when using combinatorial libraries. We present two different but complementary approaches: One approach employs a fast docking algorithm that finds low energy conformations of a ligand within an active site. The other approach analyzes the active site to develop a set of features (such as hydrogen bond donors, acceptors and lipophilic sites) that are required for attractive interactions within the active site and uses the feature set to derive pharmacophore models that are then employed in database searching to identify hits. 2:30*64. Pharmacophores including multiple excluded volumes derived from x-ray crystallographic target structures to be used in 3d-database searching. P. A. Greenridge, M. Gilner We have optimised the method of using many (>100) excluded volumes with 3D-pharmacopho-res in database searching with respect to specificity and speed (J.Med.Chem. 41:2503-2512, 1998). Structure-based pharmacophores were supplemented with exluded volumes positioned at the coordinates of the protein atoms delineating the ligand binding site. The search speed obtained makes it practically feasible to use this method, and significantly faster than reported for other softwares. The method effectively pruned the obtained hit-lists of unspecific hits (by 70-75%) . Experimental verification showed that the remaining hits were specific (had micromolar affinities). We now show for structure-based pharmacophores that this method also improves the correlation between predicted and measured affinities for a structurally diverse set of estrogen receptor ligands. The resulting regression equation may be used for scoring of database hits. 3:00*65. Docking - derived pharmacophores. R. Griffith, J. B. Bremner, B. Coban In the absence of any detailed 3D structure of adrenergic receptors, models have been constructed for the alpha1A and alpha1B subtypes of these important members of the G-protein coupled family of membrane-bound receptors. Docking of the endogenous ligand, adrenaline, and also of a rigid, alpha1A selective antagonist (IQC), developed in our laboratory, into these models will be presented. We have, in a novel application of the Catalyst software by MSI, constructed docking derived pharmacophores from the docking results. These will be presented, as well as comparisons with traditional, ligand based pharmacophores, which were developed in Catalyst using a set of subtype selective antagonists, not including IQC. The common features of "ligand" and "structure" based pharmacophores can be superimposed strikingly well. This new approach offers further opportunities for tailored ligand design. 3:30*66. A dynamic pharmacophore model for HIV-1 integrase. H. A. Carlson, K. M. Masukawa, R. D. Lins, J. M. Briggs, W. L. Jorgensen, J. A. McCammon 50-ps snapshots of a 1-ns molecular dynamics simulation of the catalytic domain of HIV-1 Integrase were used to represent the conformational flexibility inherent to the active site. Each of these protein configurations was subjected to a Multi-Unit Search for Interacting Conformers (MUSIC) simulation (a Monte Carlo, multiple-copy method available in the BOSS program). The MUSIC studies were used to develop a dynamic pharmacophore model based on the sampling of conserved binding sites for hydroxyl and ammonium functionalities in the active site of each protein model. The use of this method was validated by accurately predicting the binding site for the first of two required magnesium ions. Variations of our pharmacophore model were used to search the Available Chemicals Database. 4:00*67. Pharmacophore definition of retinoid-x-receptor modulators. S. K. White The Retinoid-X-Receptors (RXR) are homodimer and heterodimeric partners with a variety of intraceullular receptors, including PPAR, TR and VitD. While high affinity binding to the RXR's is important, we use a funtional cotransfection assay to differentiate the role of the RXR ligand. The criteria for good structure-activity correlation depends on proper choice of ligands according to biological function, pharmacophore sampling and 2D similarity. A general method of selecting ligands via biological activity profile and 2D descriptors for training sets in pharmacophore analysis will be presented. By using 2D chemical structure information to bin our ligands, we are able to create 3D pharmacophore descriptions which correlate to the activity data with R2 > 0.90. -- Osman F. Güner, Ph.D. Sr.Product Manager, Rational Drug Design Molecular Simulations Inc. (619)799-5341 osman@msi.com http://www.msi.com From chemistry-request@server.ccl.net Wed Dec 30 11:34:41 1998 Received: from www.ccl.net (www.ccl.net [192.148.249.5]) by server.ccl.net (8.8.7/8.8.7) with ESMTP id LAA15353 for ; Wed, 30 Dec 1998 11:34:41 -0500 Received: from bioc1.msi.com (bioc1.msi.com [146.202.0.2]) by www.ccl.net (8.8.3/8.8.6/OSC/CCL 1.0) with SMTP id LAA18674 Wed, 30 Dec 1998 11:28:47 -0500 (EST) Received: by bioc1.msi.com (931110.SGI/930416.SGI) for chemistry@www.ccl.net id AA14710; Wed, 30 Dec 98 08:27:33 -0800 Message-Id: <9812301627.AA14710@bioc1.msi.com> Received: from osman-pc.msi.com(146.202.7.202) by bioc1.msi.com via smap (V2.0) id xma014708; Wed, 30 Dec 98 08:27:06 -0800 X-Sender: osman@146.202.6.217 (Unverified) X-Mailer: QUALCOMM Windows Eudora Pro Version 4.0.1 Date: Wed, 30 Dec 1998 08:29:29 -0800 To: chemistry@www.ccl.net, CHMINF-L@LISTSERV.INDIANA.EDU From: "Osman F. Guner" Subject: Abstracts of Papers at ACS - Modeling@Internet Mime-Version: 1.0 Content-Type: text/plain; charset="iso-8859-1" Content-Transfer-Encoding: 8bit X-MIME-Autoconverted: from quoted-printable to 8bit by server.ccl.net id LAA15354 THURSDAY MORNING Section A Modelling and Analysis Through the Internet 1 O. Güner, Organizer, Presiding 8:30*68. Internet-based modelling and computational chemistry tools. H. Rzepa The rapid, and frequently chaotic progress made over the last five years in chemical utilisation of the Internet will be reviewed. Three issues in particular will be addressed in detail; the development of structured documents capable of storing and expressing chemical data and semantics, the use of the model rather than the image media type as an integral part of chemical documents, and issues surround the authentication of documents and chemical objects using digital certificates. 9:30*69. Dissertations from chemistry on the internet. J. Gasteiger, W-D. Ihlenfeldt, R. Hoellering An essential part of academic chemical research is performed by graduate students. Dissertations therefore offer a wealth of information that, quite often, only partly and slowly finds its way into publications in scientific journals. The implementation of dissertations on the internet provides rapid access to this cornucopia of chemical information. It can be accessed by the search technology employed for chemical databases such as name, structure, and substructure searching. Furthermore, the information in dissertations can be enriched by data derived from computations and modeling. Computer programs can be linked to dissertations to provide active contents, further enriching the importance of dissertations. 10:00*70. A structure based drug design degree course delivered on the internet. C. Burt, P. Murray-Rust, T. Brailsford, C. Edge, C. Richardson, J. Overington The paradigm of Structure-Based Drug Design (SBDD) holds the potential to increase the efficiency of the drug discovery and development process. Unfortunately, the rapid development and highly multidisciplinary nature of the process has led to a situation where many staff in the pharmaceutical industry are ill prepared to exploit effectively these techniques to the full. The Internet and the technologies of the World Wide Web (WWW) have revolutionised the way in which information may be communicated and represent an ideal platform to deliver courses to "retool" working scientists in new disciplines. The Virtual School of Molecular Sciences (VSMS) at the University of Nottingham is at the forefront in establishing virtual collaborative courses and has launched an Internet Structure-Based Drug Design Course. An overview of the course and issues related to the delivery of distance learning courses will be presented. 10:30*71. Sharing chemical information over the internet. L. R. Patiny Creating a common database over the internet on which everybody can easily contribute is difficult because it requires a lot of management. In order to circumvent this limitation, we have developed a new web server and client program allowing research laboratories to submit chemical information (name, structure, bp, mp, NMR, etc.) automatically and which they still be able to modify at a later date. This information is directly available to the rest of the scientific community. This database, containing the chemical information, can be queried from any web browser by substructure (requires JAVA), molecular formula, bp, mp, NMR shift, infra-red maxima, etc. During this presentation we will explain the concept behind this new server as well as show the way it works in practice (submitting and retrieving information). 11:00*72. Modeling and visualization on the web. M. Hahn The Web provides an ideal medium for allowing broader access to molecular modeling and molecular visualization. A key goal is to provide tools that non-computational scientists find easy to use. Ease of use, however, must be balanced with a level of sophistication such that the tools and the information they provide are not perceived as trivial. This talk describes various approaches towards building such balanced modeling and visualization environments, and describes our experiences with one such environment, WebLab. THURSDAY AFTERNOON Section A Modelling and Analysis Through the Internet 2 New Advances with Internet Software O. Güner, Organizer, Presiding 1:30*73. Webtables: computing molecular properties on the web. T. J. O'Donnell, C. J. Blankley, C. Humblet We have developed a web-based interface to assist in the task of computing and tabulating molecular properties for large sets of compounds. Data are manipulated in the form of a table with each row representing one molecule and each column representing one type of molecular property. The table is presented as an HTML page with GIF depictions of selected structures and text display of selected data columns. The major function of Webtables is to compute new columns of data. All computations are carried out on a web server Unix machine with the results returned using standard CGI methods. Data sets containing as many as 10,000 compounds are accomodated, although sizes nearer 1000 are more commonly used. The table may be output as a tab-delimited file. Data are input from a variety of input file types. We will show typical web page output for a sample session, list all available molecular property computations and discuss the underlying CGI scripting and the use of Daylight toolkit in Web Tables. 2:00*74. Chemmart: one-stop web shopping of structural databases. T. J. O'Donnell, T. N. Doman We have developed a web-based application to assist in the searching of structural databases. It allows for exact lookups, sub-structural, neighbor and SMARTS searches. In addition to searching, ChemMart can perform computations on input structures, such as clogP, "Pfizer Rule of Five" estimates, Concord 3-D coordinate generation, and polar surface area computation. Input and output is managed on a Web page using standard HTML. Structures may be sketched in, read from input files, or located by compound id number in the databases. Output may be saved in local files on the web-client computer. All searches and computations are carried out on a web server Unix machine with the results returned using standard CGI methods. We will show typical web page output for a sample session, discuss searching strategies and molecular property computations and explain the underlying CGI scripting. We will discuss the use of the ChemDraw plug-in, the Daylight toolkit, and the interface to helper applications in ChemMart. 2:30*75. Web-based integration of computational experiments with biological and chemical information. A. Shah, D. Huhta, H. Li It has long been realized that chemistry research can benefit from the integration of chemical and biological information with modeling and anlysis tools. The information can be accessed from a variety of sources, such as corporate databases and databases on the Internet. The most significant benefit of such integration is that computational analysis capabilities add value to the integrated access to chemio- and bio-informatics. Such interface of informatics and analysis provides us the much needed leverage to convert "information" into "knowledge." We will describe a client-server model as implemented in Gene Explorer and MedChem Explorer programs, in which the information from computational and information servers is seamlessly integrated. Examples will be presented that demonstrates the benefits of such an integrated Web-based environment. 3:00*76. Extending chimera for collaborative molecular visualization. T. E. Ferrin, C. Huang, T. Klein Chimera is a new, highly extensible computer application for visualizing and interactively manipulating molecular structures that is under development in the UCSF Computer Graphics Laboratory. Chimera provides for the addition of new functionality through use of a high-level programming language called Python. We have used this approach to add a prototype “collaboratory” module to Chimera for carrying out interactive three-dimensional studies of molecular structures among collaborating scientists at distant locations. With our collaboratory, multiple scientists can interactively manipulate images of shared, complex three-dimensional molecular models and interact with one another in the same way that traditional “face-to-face” collaborative scientific experiences would provide. When fully implemented, our collaboratory will not only facilitate collaborative research projects, but will provide the capability to establish interactive training sessions on molecular modeling techniques. 3:30*77. Does the web impact computer-assisted drug design. S. Krystek, W. Langton At Bristol-Myers Squibb, Web-based tools have been successfully integrated into the process for both structure and ligand based drug design. Web-based tools are being utilized in distributed environments for virtual screening, lead generation processing, compound selection, as well as for data management and the transfer of information among team members. A practical example will be presented detailing the use of Web-based tools in day-to-day activities of computer-assisted drug design. -- Osman F. Güner, Ph.D. Sr.Product Manager, Rational Drug Design Molecular Simulations Inc. (619)799-5341 osman@msi.com http://www.msi.com From chemistry-request@server.ccl.net Wed Dec 30 17:09:26 1998 Received: from www.ccl.net (www.ccl.net [192.148.249.5]) by server.ccl.net (8.8.7/8.8.7) with ESMTP id RAA15696 for ; Wed, 30 Dec 1998 17:09:25 -0500 Received: from ccl.net (atlantis.ccl.net [192.148.249.4]) by www.ccl.net (8.8.3/8.8.6/OSC/CCL 1.0) with ESMTP id RAA04309 Wed, 30 Dec 1998 17:03:29 -0500 (EST) Received: from bedrock.ccl.net (bedrock.ccl.net [192.148.249.6]) by ccl.net (8.8.6/8.8.6/OSC 1.1) with SMTP id RAA14293; Wed, 30 Dec 1998 17:03:23 -0500 (EST) Date: Wed, 30 Dec 1998 17:03:25 -0500 (EST) From: Jan Labanowski To: Michael Nolan cc: ccl , Jan Labanowski Subject: Re: Linux vs WindowsNT vs Windows95 In-Reply-To: <19981230204347.C304@rennes.nmrc.ucc.ie> Message-ID: MIME-Version: 1.0 Content-Type: TEXT/PLAIN; charset=US-ASCII On Wed, 30 Dec 1998, Michael Nolan wrote: > >Dear CCL community, > ---snip--- > > >Worrying too is the move being made by SGI (who have hitherto been > >the providers of high-end hardware for computational chemistry) to adopt > >WindowsNT as an OS (I think that I am reminded of the Blackwidow spider > >which eats its mate after mating). > > It's not just SGI. HP have also done and are doing the same thing. I would assume that DEC will go the same way, if they haven't already. This leaves, and correct me if I am wrong, SUN as the only company manufacturing workstations with their own proces sors and OS > Will we be all using Windows based OSs in the future? > > regards > > Michael > The problem from my perspective is threefold, and it really does not matter that UNIX is a better computational environment for science (you may disagree, if you are a user, and do not actually develop software. This is my perspective -- I hope I will meet some day a programmer who thinks that Windows is a better development platform for scientific applications than UNIX). 1) UNIX people could not agree on the standard and desktop environment... We are getting some CDE lately, but it is too late. Decisions are not made by computer professionals but by managers. Obviously, they like the system which they can use rather than the system (UNIX) which requires ultimate involvement. In windoz you will get there after 20 wrong clicks, in UNIX, if you do not know, you will not get there at all. 2) Microsoft makes hardware manufactures happy -- Linux can run in 16 Mbytes of RAM on 486 with acceptable speed. Windows NT needs 64 MBytes of memory minimum, and on anything less than 200 MHz pentium is a hog. Moreover, it is a black box, so the hardware vendors do not need to deal with support: "It is not our fault... Ask MS...". From the business perspective you cannot loose. Please, be reminded that scientific computing is not a business for hardware manufacturers, but a charity... 3) The important consideration is the jobs for computer professionals. If we could choose the standard, make software releases every 3 years rather than every 3 months, many people would loose their jobs. Thousands of people who fix Y2k problem need jobs in the next century. Reinventing UNIX under windoz banner (people who know the evolution path of NT 3.x, 4.0, and 5.0 know what I am talking about) is a good thing, and people will pay, since they have no choice... So do not blame HPs and SGIs for doing the right thing, since they are not in the business of making computers, but in the business of making their shareholders happy, i.e., making money... The product is always a secondary consideration... Happy New Year!!! Jan Labanowski's private views at this moment... My employer does not even know what I wrote... jkl@ccl.net