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Frequently Asked QuestionsGeneral questions about MultiCASE products
QSAR
MCASE/MC4PC/CASETOX
METAPC
InfoTox
OpenVMS/AXP specific information
General questions about MultiCASE products
How can your software predict whether my chemicals are toxic (carcinogenic, mutagenic, etc.)?To predict whether your chemicals are biologically active in a specific endpoint you must have a database for that assay. For example, to predict carcinogenicity in rodents you need access to one or more databases for carcinogenicity. When you test a chemical against that database, our software (MCASE or CASETOX) searches the structure of the chemical for the presence of one or more biophores. If a biophore is present, then MCASE predicts the chemical is active, and if no biophore is found MCASE predicts the chemical is inactive. Typically a given biophore will be found in some inactive molecules as well as active molecules. The distribution gives a statistical measure of the predictive value of the biophore. For example, if the database contains 50 nitrosamines, and all of these are active, then presence of the N-N=O biophore is a very strong predictor of toxicity. On the other hand, if only half of the nitrosamines in the database are active and half are inactive, then we can only be 50% confident that chemicals containing N-N=O are active. Back to Top
Do I need special knowledge to use Multicase software?The user interfaces for our PC-compatible programs are designed to be "user friendly", and a person who is familiar with the usual software for Microsoft Windows such as Microsoft Word, Excel, and ChemOffice will have little difficulty using our programs. It is helpful but not necessary to have experience using some type of computer database. Naturally, the user must have some scientific background in organic chemistry, toxicology, and pharmacology. Back to Top
What are the prices for Multicase products?Please contact us by phone or e-mail and we’ll send you a list of approximate prices for our software and databases. If you reach a stage where you have decided to purchase our products, contact us again with a specific list of what you want to buy, and we will send a detailed price quote. Back to Top
What does a license include? Do we need to renew it every year?Multicase sells a one-year license for its software products, which includes the cost of upgrades, maintenance, and technical support. The license is for use on a single processor, although we can offer a discount for use on additional processors. Databases are sold for a one-time fee, but users may choose to purchase upgrades when they become available. Back to Top
I only have a few chemicals that I need to test to see whether they are toxic (mutagenic, carcinogenic, etc.). Can you test these for me so I don’t need to invest in your software?Persons that wish to test a small number of chemicals without purchasing our software can use some of our services or lower cost limited versions of our products. Back to Top
What platform or platforms are supported for Multicase software?Our software is now available for PC/Windows platforms. The original versions of our programs (MCASE, CASETOX, and META) were developed for the Alpha/OpenVMS platform. The Alpha/OpenVMS versions run on Compaq Alphastations such as the XP900 or XP1000 series. As of May 15 2003, we discontinued development for the Alpha/OpenVMS platform and ship all of our products designed for PC/Windows platform. Back to Top
How is the PC version of MCASE different from the Alpha/OpenVMS version?The PC versions of our software have different graphical user interfaces (GUIs) from the corresponding Alpha/OpenVMS versions, but the underlying program logic and algorithms for bioactivity prediction are unchanged. This means the PC versions have a different look and feel from the OpenVMS versions, and perhaps they are more convenient for persons who are accustomed to using the Windows platform. However, the bioactivity prediction using MCASE or CASETOX will be exactly the same as the prediction with MC4PC or TOX4PC using the same database. Similarly, a tree of metabolites predicted with META is identical to that predicted by META-PC. Back to Top
Will the Windows/PC version of MCASE give the same biophores as the OpenVMS version?The PC and OpenVMS versions of our software use exactly the same algorithms for making QSAR predictions. Therefore, a biophore predicted by MCASE or a metabolite predicted by META will not depend on which platform you are using. Back to Top
What are system requirements for the PC versions of your software?The Minimum system requirements for the PC compatible platform are Pentium III processor (800 MHz), 256 Mb RAM, 6 Gb hard disk space, and Windows NT/2000/XP operating system. Back to Top
I understand Multicase has collaborated with the U.S. Food and Drug Administration in building some toxicity databases. What types of databases are these?The FDA Center for Drug Evaluation and Research (CDER) has worked with Multicase to build databases for carcinogenicity in rodents, teratogenicity, maximum tolerated dose, mutagenicity and adverse effects. These can be used on both the PC/Windows and OpenVMS platforms. Back to Top
What is the difference between the proprietary and nonproprietary FDA/Multicase carcinogenicity modules?The proprietary modules contain the same set of chemicals as the nonproprietary modules, and in addition they contain some proprietary chemicals. The nonproprietary databases are fully accessible, and allow MCASE or CASETOX users to know the identities and properties of every chemical. In the proprietary modules the structures and names of the proprietary chemicals are hidden. Users are unable to modify or add to the proprietary databases. Back to Top
QSARWhat is QSAR?QSAR stands for Quantitative Structure-Activity Relationship. The name means what it says, that a relationship exists between chemical structure and activity. "Activity" can mean a physical property such as solubility, boiling point, octanol/water partition coefficient, etc.. "Activity" in applications to toxicology and pharmacology means biological activity, such as antibacterial or antiviral activity, mutagenic potentency, carcinogenic potency, etc.. Indeed, the definition of activity is easily blurred, and one of the objectives of QSAR research is to find an objective, quantitative measurement that applies to important concepts like teratogenicity or biodegradability. The concept of QSAR has historic origins in Physical Organic chemistry, which uses linear free energy relationships to describe reaction rates and equilibria. Many, many examples can be found in the published chemical research dating back to the 1950s, of the use of Hammett substituent parameters and other chemical descriptors to describe chemical and physical phenomena. Back to Top
What is a biophore?A biophore is a structural fragment that is statistically related to biological activity. For example, presence of the N-N=O (nitrosamine) fragment is strongly correlated with mutagenicity in both aromatic and aliphatic chemicals. "Toxicophore" and "pharmacophore" are related terms, applied to biophores that are connected with some toxic or therapeutic endpoint. The term "structural alert" has also been applied in computational toxicology, meaning a chemical fragment that is a warning signal for a toxic endpoint (especially mutagenicity). Back to Top
What is a distance descriptor?A distance descriptor is a structural feature consisting of two atoms or groups that have a fixed spatial distance from each other. The number and type of atoms and bonds that separate the two end groups of a distance descriptor are indeterminate.
How is a distance descriptor different from a biophore?A distance descriptor can have the same role as a biophore, as a predictor biological activity. However, a distance descriptor is structurally different from biophores and other fragments, which are connected linear chains of atoms or groups. Back to Top
What is the difference between a global descriptor and a nonglobal descriptor?A global descriptor is a property of a chemical such as LogP, graph index, or molecular weight. A nonglobal descriptor is a substructure or fragment imbedded in a molecule. Back to Top
What is a SMILES code?SMILES is a line notation used for encoding the 2-dimensional structures of organic molecules. A couple of simple examples are benzene, which is coded as c1ccccc1, and acetone, which is coded as CC(C)=O. SMILES is used to encode molecular structures for Multicase databases. SMILES codes used with our software should be preceded by "-S" (i.e. –Sc1ccccc1 for benzene), and should be no longer than 180 characters. Also, our program does not accept salts or clusters containing more than one molecular fragment. More information about SMILES codes including a tutorial is available at the following web site: http://www.daylight.com/smiles/. Back to Top
What is KLN?KLN stands for "Klopman Line Notation". KLN is like SMILES code, an abbreviated line notation for describing 2-dimensional molecular structures. KLN was developed specifically for use in computational toxicology, so that it is a convenient notation for use with our software. Back to Top
What is LogP?LogP is the base-10 logarithm of the octanol/water partition coefficient. The partion coefficient for a chemical is defined by P = Coct/Cwater, where Coct and Cwater are equilibrium concentrations of the chemical in the upper octanol layer and lower water layer under standard conditions (25 degree celcius, atmospheric pressure). Back to Top
Why is LogP important?Octanol/water partitioning is an index of the general distribution of a chemical between aqueous and lipid environments. As a measure of lipophilicity, LogP is a very important global descriptor that gives an indication of the ability of a chemical to cross the cell membrane. The membrane can be regarded as a lipid bilayer separating two aqueous compartments. Hydrophilic substances having a very small LogP are generally unable to diffuse passively across the membrane into the cell. Lipophilicity has further consequences for bioavailability in mammals because of partitioning between the blood and fatty tissues. Back to Top
How is MCASE different from other algorithms for quantitative structure-activity relationships (QSAR)?MCASE stands for Multiple Computer Aided Structure Evaluation. The name gives a key to why our algorithm is unique. In all other QSAR algorithms, the user must construct a set of descriptors and then predict the activity of other chemicals based on those descriptors. The descriptors can be structural fragments or global properties (lipophilicity, molecular weight, etc.). The algorithm gives no clues about how to construct the set of descriptors, and indeed this is a difficult task. The MCASE algorithm builds a set of QSAR descriptors automatically, with no decision making on the part of the user. The only necessary inputs from the user are a list of structures along with their biological activities. Of course, the quality of the resulting database is dependent on the quality of the input data (i.e. garbage-in means garbage-out). If the input data contains a strong statistical basis for a relationship between chemical structure and biological activity, then MCASE will discover that relationship automatically. Back to Top
MCASE/MC4PC/CASETOXWhat is the difference between CASETOX and MCASE?The only difference is that MCASE allows users to create or modify databases while CASETOX does not. CASETOX users must purchase databases supplied by Multicase. If CASETOX and MCASE are used with the same database, the results will be identical. If you want to build a database from your in-house data, you must have MCASE. On the other hand, if you only want to screen chemicals for some toxic endpoint (e.g. carcinogenicity in rodents), you can use CASETOX along with our databases. Back to Top
How is LogP calculated by MCASE?Our algorithm for computing LogP is based on a multiple linear regression fit to experimentally known LogP values for a large number of diverse chemical structures. The regression variables are structural descriptors, such as methyl, hydroxyl, amide, etc.. Methyl and other hydrophobic groups make a positive contribution to LogP, while hydroxyl and other hydrophilic groups make a negative contribution. LogP values for other chemicals not included in the regression data set are computed using the fitted parameters. Back to Top
We have tested a batch of 1000 chemicals and we would like to see a summary of the results. Is there any way to do that?For both the OpenVMS and Windows/PC versions a summary of results is found in the Jnn.dat file. This file has a one-line record for each chemical in the test file, that reports the experimental activity, the predicted activity, and the probability that the chemical is active. If your test file contains 1000 chemicals, then the Jnn.dat file will contain 1000 lines, one for each chemical that you tested. A 2x2 contingency table found at the very end of the Jnn.dat file gives an idea of the quality of the test results in a single glance. This table is also very useful for doing database validations. Another file named Rnn.dat gives a more verbose output of the test results. This file gives a detailed output for each chemical, that includes the biophore(s) responsible for any observed activity, a list of modulators (if any), a prediction about bioavailability based on Lipinski’s rule of five. Also, a list is generated if any structural fragments are found in the tested chemical that are unknown to the learning set. Back to Top
The size of my database is limited to 3,000 chemicals, but I want to do computer screening on a much larger library, containing 50,000 chemicals. How can I do this?The number of chemicals in the database has nothing to do with the number of chemicals in the test file. A database is limited to 3,000 chemicals, but the number of chemicals in a batch testing file is unlimited.
How can I create a batch testing file for 10,000 chemicals?The ascii file will be identical for both the OpenVMS and PC/Windows versions. The file will contain 10,000 records. Each record should have four fields: (1) CAS registry number (if unknown use 0), (2) activity in CASE units or other units, (3) SMILES code, (4) name of chemical. Back to Top
I understand there are special instructions for using FDA carcinogenicity modules. Can you explain this?The standard MCASE program makes predictions based upon information in a single control database module (male rat, female rat, male mouse, or female mouse), and does not integrate data from several modules. Researchers at the FDA/CDER modified this evaluation paradigm by comparing the biophores identified in the individual modules. Biophores from each of the related rodent carcinogenicty modules (e.g. AF5-AF8) are compared and a subset of transgender and transspecies biophores is identified. The rank-order of the biologic potency of MCASE biophores is: gender-specific << transgender << trans-species. Classification of biophores according to their biological as well as their statistical significance increases the sensitivity of the analysis. For more details, you can refer to the following publication: "A New Highly Specific Method for Predicting the Carcinogenic Potential of Pharmaceuticals in Rodents Using Enhanced MCASE QSAR-ES Software." Matthews, Contrera. Reg. Tox. Pharm. 28, 242-264 (1998). Back to Top
I don’t understand the notation used for biophores and other fragments. Will you please explain it?Don’t confuse our notation for biophores, distance descriptors, and other fragments with SMILES or KLN codes. The notation for fragments is completely distinct from the code for molecular structures. For a person who has some background in organic chemistry, the notation for fragments shouldn’t be difficult to understand. Here are a few points to remember. (1) Lower case letters are used for aromatic elements. For example the fragment NH -c =cH -cH =c -c. = codes for an aromatic amine. (2) The carat (^) symbol denotes an atom that is part of a small ring (three or four atoms). For example, the fragment C –N^ codes for an aziridine and O^ -CH2 codes for an epoxide. (3) A period (.) following an atom means the atom is found at the junction of two rings. For example, the code c =cH –cH =c. indicates the fragment is made of four aromatic carbons, with the last carbon being at a ring junction. This fragment can be found, for example, in naphthalene or other fused aromatic systems. (4) For persons who are used to writing organic structures, the presence or absence of hydrogens means exactly what you would expect. In the previous example, the first carbon is substituted, and the second and third carbons are unsubstituted. (5) A quote (") following an atom label means the atom is double bonded to an atom not included in the fragment. For example, in the fragment C -C." –CO the second atom is a quaternary carbon found at a ring junction (notice the period), that is double bonded to another atom (most likely carbon) that isn’t shown. Notice the third component of the fragment is CO (carbonyl), so the system is a conjugated carbonyl (Michael acceptor) embedded in a fused ring system. (6) c> (lowercase carbon followed by greater than symbol) indicates the aromatic carbon is bonded to an electron withdrawing substituent such as a nitro group. Similarly c< (lowercase carbon followed by less than symbol) indicates the aromatic carbon is bonded to an electron donating substituent such as an amine or hydroxy group. (7) Substituents are indicated by <X>, where X is a substituent such as methyl, chloro, fluoro, amino, carbonyl, etc.). For example, the notation <5-CH3> is used to show that the fifth atom of the fragment is substituted by a methyl group. As a final point, notice our definition for fragments makes some provisions for branching, but is focused on identifying linear chains of atoms. Back to Top
I see a biophore in my database that has a carbon followed by a quotation mark (i.e. C"). What does this mean?A quote (") following an atom label means the atom is double bonded to an atom not included in the fragment. The identity of the second atom of the double bond is not specified; the C" most likely indicates a carbonyl or an alkene. Back to Top
I see a fragment in my database that has an oxygen followed by a carat mark (i.e. O^). What does this mean?The carat (^) symbol denotes an atom that is part of a small ring (three or four atoms). For example, the fragment C –N^ codes for an aziridine and O^ -CH2 codes for an epoxide. Back to Top
I see a fragment in my database that has lower case carbon followed by a greater than symbol (i.e. c>). Why is the carbon lower case, and what is the greater than symbol?Lower case symbols are used for elements that are part of an aromatic ring. c> (lowercase carbon followed by greater than symbol) indicates the aromatic carbon is bonded to an electron withdrawing substituent such as a nitro group. Similarly c< (lowercase carbon followed by less than symbol) indicates the aromatic carbon is bonded to an electron donating substituent such as an amine or hydroxy group. Back to Top
I see the following fragment in my database c." -CO. What is the meaning of the ." (period followed by quote).The period (.) is used to indicate an element that forms a ring junction. In the fragment c." -CO the first atom is a quaternary aromatic carbon found at a ring junction (notice the period), that is double bonded to another atom (most likely carbon) that isn't shown. Notice the second component of the fragment is CO (carbonyl), so the system is carbonyl conjugated to an aromatic ring. Back to Top
I would like to have a summary of the biophores and distance descriptors in my database. Can MCASE generate this information?The information you need is contained in the "Snn.dat" file that is automatically created during processing of a database. This is an ascii text file that contains statistical information about each biophore. The same file is created for both the OpenVMS and PC/Windows versions. It will be found in the same directory as the other database files (typically this is the [MCASE.DATA] directory for OpenVMS or the \MC4PC\DATA\ directory for Windows). Back to Top
What does it mean when the program gives a list of redundant fragments?Sometimes the MCASE algorithm finds that a biophore is redundant with another fragment or a group of fragments. This means that all molecules containing the biophore also share one or more other fragments. Presence of redundancy casts doubt on the predictive value of the biophore, because it is not statistically possible to say with certainty which fragment is responsible for bioactivity. Back to Top
What does it mean when the program gives an expanded definition for a fragment?An expanded definition for a fragment gives a "fuzzier" meaning to the fragment, in which structurally similar fragments are grouped together. For example, the NO –N (nitrosamine) fragment can be expanded to include similar groups such as CO –N (amide), SO –N (sulfonamide), and NO2 –N (nitramine). Sometimes the expanded definitions might seem to stretch the truth a little, but we try to be thorough. Another example is the fragment Br –CH2 (primary bromide), which can be expanded to include Br –C (tertiary bromide), Br –CH (secondary bromide), Cl –CH2 (primary chloride), and even Cl –NH (chloramine). Expanded definitions are very useful, because the expanded list of fragments can be used form a much stronger statistical basis for a structure-activity relationship. To put it another way, the biophore along with its set of expanded fragments can be grouped together to form a more general definition for the structural moiety that is responsible for bioactivity. Back to Top
I have tested a molecule and MCASE tells me it contains an unknown fragment. What does that mean?An unknown fragment is one that does not exist in any molecule in the database. If you test a chemical that contains an unknown fragment, MCASE has no basis for deciding whether the fragment might cause biological activity. If you are testing a large and structurally diverse library of chemicals, then the database must be correspondingly diverse. Otherwise, most of the tests will be inconclusive due to presence of unknown fragments. Back to Top
We have just received an upgraded version of MCASE. Can we still use our databases that were built with the older version?It will be necessary to RESTART all the databases that have been developed with versions older than 3.3. It is recommended that you RESTART the databases developed with later versions as well so as to assure consistency of your data. UNDER NO CIRCUMSTANCES SHOULD YOU TRY TO RESTART DATABASES CONTAINING PROPRIETARY DATA e.g.FDA F5 to F8. Please contact us at service@multicase.com if you have problems. Back to Top
The following smiles code: c21c3c([nH]c1c(ncn2)Cl)cccc3 was generated by a SYBYL UNITY transform to Daylight SMILES. MCASE complains about [nH] and asks me to change it. Why is this?you will have to replace [nH] part by n, so the final string will look like c21c3c(nc1c(ncn2)Cl)cccc3. Please be advised that currently MCASE does not support extended SMILES notation ( characters like /,\, [,],@, etc.). Our the built-in SMILES checker subroutine will detect these characters and remove or replace them automatically. In addition, MCASE does not support ionic salts, nonbonded clusters of molecules, structures with more than 10 rings, or SMILES codes longer than 180 characters. Back to Top
How can we find out whether our database is good or bad?The best method for validating a database is to test a set of chemicals that are not contained in the database. If the database is good, it will give a high percentage of true predictions for both active and inactive chemicals. Naturally, only chemicals that have been tested experimentally can be used in the validation. Back to Top
I tested a batch of chemicals against my database and the results are terrible. What should I do?Sometimes the database can be improved by adjusting the fractions of active and inactive chemicals in it. Common sense suggests that if 90% of chemicals in the database are inactive, then the model will naturally predict most chemicals are inactive. For best results, it is best to adjust the dataset so that it contains approximately a 50/50 mixture of active and inactive chemicals. The ratio of active/inactive chemicals can also be adjusted by changing the breakpoint. Another possible reason that the database performs poorly is that it doesn’t contain enough structural diversity. The MCASE model is only as good as the information you put into it. For example, suppose you create a toxicity model using data only for aliphatic chemicals. if you ask the database to give a prediction about toxicity of an aromatic amine, the model naturally has no basis to make a prediction. It is not always possible to create a good database, because sometimes there is no relationship between chemical structure and biological activity, or because the available experimental data is too scarce to construct a statistically robust model. Back to Top
I tested a batch of chemicals against multiple databases. How can I see a summary of the test results?For both the Windows/PC and OpenVMS versions, the results are in two files called "Nxx.dat" and "Oxx.dat". The letters "xx" are determined by the name of the test file. For example, if the test file is "DM1.dat" then the output is stored in "NM1.dat" and "OM1.dat". If the test file is an ascii file (not a Dnn.dat file), the output files will be named "NOO.dat" and "OOO.dat". "OOO.DAT" gives a verbose description of the test results (analogous to "RNN.dat")and "NOO.DAT" gives a brief summary. Back to Top
I want to test a chemical against some (but not all) of the databases in my [MCASE.DATA] directory. How can I do this?For the Windows/PC version, just select the databases with the mouse while holding down the control key. Notice you should be in "Test Molecules" mode. For the OpenVMS version, after you choose option "M" for multiple testing, the program gives the prompt "which database do you wish to scan [*]...". By default, the program will test against all databases in the current directory (i.e. [*]). If that's what you want, then press the RETURN key. To test against only a few selected databases, enter the names of the databases separated by commas. For example, to test against AF1- AF4 you will enter "F1,F2,F3,F4". Notice the first letter "A" should be omitted. Back to Top
How should I select the databases for doing multiple tests?For the Windows/PC version, just select the databases with the mouse while holding down the control key. Notice you should be in "Test Molecules" mode. For the OpenVMS version, after you choose option "M" for multiple testing, the program gives the prompt "which database do you wish to scan [*]...". By default, the program will test against all databases in the current directory (i.e. [*]). If that's what you want, then press the RETURN key. To test against only a few selected databases, enter the names of the databases separated by commas. For example, to test against AF1- AF4 you will enter "F1,F2,F3,F4". Notice the first letter "A" should be omitted. Back to Top
We have a set of 1000 structures stored as MDL .mol files, and I want to test these structures using CASETOX. How can I do this?CASETOX (or MCASE) supports batch mode input of structures stored in MDL .mol format. This option is available only on the Alpha/OpenVMS platform. The PC platform permits data entry from a .mol file, but only for a single structure and not a batch of structures. To do this on the Alpha/OpenVMS platform, you must create a master file that contains one record (i.e. one line) for each .mol structure. The master file is an ascii text file that points to the set of .mol files. A master file containing 1000 lines is needed for testing 1000 structures in .mol format. Each record contains four fields, for CAS number, activity, structure (i.e. name of .mol file), and chemical name. If the activity is unknown you should use a dummy value such as 1, and if the CAS number is unknown enter zero. The name of the .mol file should be preceded by "-M" (hyphen followed by uppercase letter M). The "-M" string allows the program to distinguish the .mol format from SMILES or KLN formats. Structures coded in SMILES should be preceded by "-S" and structures coded in KLN do not require any marker string. Mixing SMILES, KLN, and .mol formats in the same ascii file is allowed. Back to Top
How can we enter the structure for a sodium salt into MCASE?MCASE does not support salts. Salts such as ammonium salts or alkali carboxylate salts can be represented as the corresponding neutral compounds (amines or carboxylic acids), assuming the counterion has no important role. Back to Top
My structure contains two large fragments, and MCASE won't accept it. What should I do?MCASE won't accept structures such as molecular clusters, hydrates, and other structures having two or more unconnected fragments. If the structure contains more than one fragment, it is often possible to choose a key fragment to use for MCASE analysis. For example hydrates can be represented in their dehydrated form, assuming that bound water molecules don't have any key role in the biological activity. In your situation, either one of the two large fragments could be the cause for biological activity. The way to handle this is to enter the fragments as two separate chemicals in the database. Don't try to use the same CAS number for both chemicals, because the program won't like this either. Back to Top
What is the meaning of the symbols (+) and (-) in the Jnn.dat file?The (-) symbol indicates that the prediction is negative, but the decision is not clear cut. Similarly the (+) symbol indicates the prediction is positive but the decision is not clear cut. One cause for ambiguity is the presence of unknown fragments. The decision will also be uncertain if the molecule contains a biophore that is not statistically good because it is redundant with other fragments. Back to Top
What causes the result of a test to be inconclusive?Results from a test are labeled inconclusive if the molecule contains more than two unknown fragments, or the molecule contains a biophore that is not statistically significant or exists in a significantly different environment than in the database. Back to Top
Why does the program predict that my molecule has marginal activity when it has a highly significant biophore?The biophore establishes a baseline activity prediction that can be increased or decreased by modulating fragments or global properties such as LogP, large size (i.e. high molecular weight), or electronegativity. Back to Top
How can we speed up the processing time for our large database?Assuming you are using DECRam (which all OpenVMS/AXP MCASE users should do), during processing of a large database, a large data file is stored on the RAM disk. If the RAM disk is not large enough to store the file, the program will switch out of RAM. This means that reading and writing is much slower (by a factor of about 10). If you have extra memory available, the problem is easy to correct by increasing the size of the RAM disk. Otherwise, it might be necessary to purchase additional memory, which is not very expensive. For the PC/Windows version, processing can be speeded up by (1) using a faster processor, and (2) installing extra memory. We recommend using at least a Pentium III processor and 256 MB RAM. Back to Top
Is it possible to save my test results in a different directory from the [MCASE.DATA] directory?In the current Windows/PC version you can use "Change working directory" menu command to set up the output directory. For the OpenVMS system if you start MCASE from directory [.DIR1] then test output will be stored in that directory. You can open a database in another directory [.DIR2] by using the "D" option to change directories, but output and test files will still be read from [.DIR1]. Back to Top
What is the difference between the A2I database for mutagenicity and the A2K-A2Z databases?The A2I database gives a measure of global mutagenicity in all strains of S. Typhimurium. It is a binary database, in which chemicals are classified categorically as active or inactive, without considering mutagenic potency. This means that a chemical that is very highly mutagenic in the Ames test is considered to be no more active than a chemical that is only moderately mutagenic. The A2K-A2Z databases correspond to mutagenicity in five separate strains of S. Typhimurium (TA97, TA98, TA100, TA1535, TA1537). The databases are further separated on the basis of presence or absence of metabolic activation (S-9). Activities of chemicals in the A2K-A2Z modules are based on a continuous scale of mutagenic potency, ranging from 10 CASE units (nonmutagenic) to 80 CASE units (very highly mutagenic). This means that screening a chemical against the A2K-A2Z modules can provide detailed information about mechanism and mutagenic potency, while the A2I module gives a yes or no decision about mutagenicity. Back to Top
We are trying to build a database and I get an error message that says "Inconsistency in NRMOL in FRBIO", and then the program crashes. What is going on?MCASE cannot build a database if two or more records share the same CAS number. This is the cause for the inconsistency. The only exception is that duplicate records are allowed having zero (0) for the CAS number. To correct the problem, you must edit the Dnn.dat file and locate the entries that share the same CAS number, then you must either delete all except one of the duplicated entries, or change the CAS numbers for the duplicated entries to zero. Back to Top
Users in our group cannot access one of the databases. What is the problem?Probably the file protection settings are wrong. If protection settings for the group don't allow read and write permissions, then MCASE users will not be able to access those files. To correct the problem, ask the system administrator to change the file permissions. Back to Top
METAPCWhat does the META program do?META (or META-PC) is used to predict the products formed during metabolic breakdown of organic chemicals. The user of META enters a chemical structure, and the program automatically generates a branching tree of metabolites. The first branches on the tree are primary metabolites formed from the parent chemical. Each primary metabolite can give rise to secondary metabolites, each secondary metabolite can form tertiary metabolites, and so on. This information is useful because many chemicals are not biologically active, but can form biologically active metabolites. Back to Top
What is a META dictionary?The META (or META-PC) program cannot predict metabolic products by itself, but it must have an accompanying dictionary. The dictionary is a compilation of known enzymatic transformations, that form a basis for predicting how a test chemical will be metabolized. Back to Top
What dictionaries are available? What is the difference between them?Currently four dictionaries are available for the PC/Windows or OpenVMS version of META, for mammal metabolism, aerobic metabolism, anaerobic metabolism, and photodegradation. The mammal metabolism dictionary is the correct choice if you’re interested in ADME/Tox profiles for a chemical. The aerobic and anaerobic dictionaries apply to degration by bacteria, and are useful for studies related to ecotoxicity. The photodegradation dictionary is intended for use in predicting degradation products of drugs and other chemicals when they are stored on the shelf. Use of one of these databases is required in order to run the program. Back to Top
What is the MESP dictionary?The MESP dictionary is supplied automatically to META users, and its use is entirely automatic and transparent. It is used to handle the situation in which a metabolite is formed undergoes a spontaneous (i.e. nonenzymatic) transformation. A common example is formation of an enamine or enol, which undergoes spontaneous tautomerization to the corresponding imine or ketone. Back to Top
INFOTOXCan I access the FDA databases online at the Infotox site?Yes, some of the MCASE/FDA databases are accessible online for Infotox account holders. Back to Top
How does online testing with the Infotox site differ from testing with the MCASE or CASETOX programs?Infotox is different from MCASE/CASETOX in several ways. Infotox is an online internet interface to our software. The user enters the structure of a test chemical, and chooses from a list of available databases. After submitting the chemical, the user receives a detailed output about the biological activity of the chemical. The Infotox user is not able to find out characteristics of the database. MCASE and CASETOX are software packages which are purchased and used at your work site. Using MCASE or CASETOX a user can create a list of chemicals in the database, a list of biophores in the database, and a list of modulators associated with each biophore. Also, the user can create a list of molecules that contain a particular biophore or other fragment. None of these things are possible for users with an Infotox online account. Back to Top
Can Infotox be used for batch testing?No. Chemicals screened online through an Infotox account must be screened one at a time. To screen a large chemical library in batch mode, you must have access to MCASE or CASETOX at your work site. Back to Top
OpenVMS/AXP specific informationQuestion:We have just received a diskette to renew our MCASE OpenVMS software license. What do we do now?Installation of the updated license is very simple. Log on to the VAX as system manager, and type SET DEF [MCASE.EXE]. Now insert the diskette into the ALPHA’s floppy drive slot and type MOU DVA0: MCASE to mount the floppy disk. Then type COPY DVA0:[MCASE.EXE] */LOG, to copy the contents of the floppy disk to the [MCASE.EXE] directory. Ordinarily the floppy disk has three files on it that will be copied to the hard drive: LICENSES.SYS, CASE.SYS, and MC_SYS.DAT. After copying the files, dismount the floppy drive by typing DISM DVA0:. Finally, remove the floppy disk and store it as a backup. If something goes wrong, report the problem to MULTICASE and give as many details as possible. Back to Top
We received some of the new MCASE/FDA data modules on a CDROM. What do we do now?Installation of the new databases on the OpenVMS platform is similar to installation of an updated license. First insert the CD-ROM into the ALPHA’s CD drive slot and type MOU DQA0:/override=id to mount the disk. The CD has an executable program which will install the databases. To run the program, type RUN DQA0:[000000]UPDATE. The new database files and a CASE.ADD file will be copied to the [.DATA] directory. Dismount the CD by typing DISM DQA0:, and remove the CD and store it as a backup. You must now add the data from the CASE.ADD file to the end of the CASE.DAT file. First, change to the [.DATA] directory by typing SET DEF [.DATA]. Then type COPY CASE.DAT,CASE.ADD/CONC CASE.DAT, which will perform the concatenation. You should now be able to run MC with the new databases. It is not necessary to reprocess any databases unless you also receive a program update with instructions to update the databases. If something goes wrong, report the problem to MULTICASE and give as many details as possible. Back to Top
What files do we need to renew our OpenVMS MCASE license?For the usual case, you will need the files LICENSES.SYS, CASE.SYS, and MC_SYS.DAT. These will be placed in the same directory as the MCASE executable file. Additionally, if you are receiving new databases you will need to modify your CASE.DAT file by adding a new line for each database. Back to Top
We have switched from the Alpha/OpenVMS to the Windows/PC version of MCASE. How can we transfer our databases over to the PC?If you have the OpenVMS data in an ascii text file, then you can use the file to rebuild the database on your PC. The Alpha/OpenVMS and Windows/PC versions will read the same ascii file, which can be used to create a new DNN.DAT file. However, if you are using CASETOX or you have a DNN.DAT file but not an ASCII file, then it will not be possible to transfer the data. In that case, please contact us to arrange for transfering the data. Back to Top
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