Daniel W. Zaharevitz, Frederick Biomedical Supercomputing Center, Developmental Therapeutics Program, PRI/DynCorp
Introduction
Chem-X is a molecular modeling and database program. It is a product of Chemical Design, Ltd. Chemical Design can be contacted at:Roundway House, Cromwell Park, Chipping Norton, Oxfordshire OX7 5SR UK Tel: (0608)644000 FAX: (0608)642244 200 Route 17S, Suite 120 Mahwah, NJ 07430 USA Tel: (201)529-3323 FAX: (201)529-2443
This document attempts to explain a few Chem-X features that are modified at the NCI. Parts of these explanations follow closely the cited parts of the Chem-X Reference Manual, which should be consulted for a much more through and detailed explanation. Of course, if Chemical Design made their manual Web accessible then I could just put hot links to their pages ( HINT, HINT).
Parameterization
Parameterisation in Chem-X is fully discussed in Chapter 15 of the Reference Manual. The default parameters are found in $CDL_FILES/extended.mmp. The associated parameterisation database is $CDL_FILES/extended.dbs. At the NCI we have added two platinum atom types to the parameterisation by running the addpt.log script. Note that we don't add all the bond length and bond angle parameters, because without the ChemInorganic module we really can't do much modeling of Pt compounds. There are no changes or additions to the parameterisation database, so we just create an empty database with the new parametisation and copy the old segments to the new database. The parameter file and the associated database is kept in the $CDL_USERFRAG directory and is automatically loaded on startup by calls in the $CDL_CHEMX_MANAGER/chemx.ini file.
Generating Conformations
Generating conformations in Chem-X is documented in Chapter 21 of the Reference Manual. The first step is to determine the bonds to be rotated. Chem-X will determine this automatically. Terminal bonds ( for example, C-H ) are excluded as are bonds to terminal groups ending in identical atoms ( for example, -CH3, -OH, -CF3 ). Bonds that are in rings are excluded by default, but they can be included. We have found the Chem-X ring conformation search to be unacceptably slow for large database purposes and we routinely exclude ring bonds from consideration. The number of points to be considered around each rotatable bond is determined by the bond type. This parameter can be set independently for the four different bond types:- single bonds
- alpha ( sp2- sp3 ) bonds
- conjugated single bonds
- double bonds
Evaluating Conformations
Each conformation that is generated is evalauted and a decision made as to whether to keep or discard the conformation. Obviously it would be ideal to make this decision based a a detailed energy calculation, but a rule-based approach ( Reference Manual, Section 21.4.3 )is the only practical possibility for large databases. The rule based approach is based on the work of Dolata ( Dolata, D.P., et. al. J. Comput.-Aided Mol. Des., 1987 , 1,73-85.) A rule is defined in terms of three central torsion angles occuring in a six atom chain. The possible torsion angles are divided into a set of six ranges and each range is represented by a letter. For single, conjugated single, or double bonds the ranges are labeledsingle, conjugated single, double bonds
and for alpha ( sp2 - sp3 ) bonds
alpha bonds
For example, n-hexane with the interior C-C bonds fully eclipsed would be described as aaa while the fully extended, all trans geometry would be described by ddd. A rule is a description of which atom type are in the six atom chain and a list of torsion angle combinations that are considered high energy. There are four levels of rules: soft, medium, hard and very hard. A conformation is rejected if it is listed in:
- one or more hard or very hard rules
- two or more medium rules
- four or more soft rules
- one medium rule and two soft rules
- all upper case indicate a very hard rule
- two upper case and one lowercase indicate a hard rule
- one upper case and two lower case indicate a medium rule
- all lower case indicate a soft rule
H/C+4/CSP2/C+4/C+4/*/ Khb/jhb/Ihb/hhb/Ghb/lhb/kgb/Jgb/igb/Hgb/ggb/Lgb/kla/jla/ila/hla/gla/lla/KKa/ - JKa/IKa/HKa/GKa/LKa/KJa/JJa/IJa/HJa/GJa/LJa/kia/jia/iia/hia/gia/lia/KHA/JHa/ - IHA/HHa/GHA/LHa/KGa/JGA/IGa/HGA/GGa/LGA/Khf/jhf/Ihf/hhf/Ghf/lhf/kgf/Jgf/igf/ - Hgf/ggf/Lgf/kle/jle/ile/hle/gle/lle/KKe/JKe/IKe/HKe/GKe/LKe/KJe/JJe/IJe/HJe/ - GJe/LJe/kie/jie/iie/hie/gie/lie/KHE/JHe/IHE/HHe/GHE/LHe/KGe/JGE/IGe/HGE/GGe/ - LGE/Khd/jhd/Ihd/hhd/Ghd/lhd/kgd/Jgd/igd/Hgd/ggd/Lgd/klc/jlc/ilc/hlc/glc/llc/ - KKc/JKc/IKc/HKc/GKc/LKc/KJc/JJc/IJc/HJc/GJc/LJc/kic/jic/iic/hic/gic/lic/KHC/ - JHc/IHC/HHc/GHC/LHc/KGc/JGC/IGc/HGC/GGc/LGC/
The 3D distance keys
Chem-X uses keys as a way to rapidly screen out compounds that could not possibly satisfy a query. Keys are discussed in Chapter 29 of the Reference Manual. There are three types of keys in Chem-X:- formula key - number of various classes in the molecule, such as hydrogen bond acceptor, halogens, oxygens, etc. see Appendix L.2 in the Reference Manual.
- bond key - number of various bond patterns in the molecule. see Appendix L.3 in the Reference Manual
- 3D distance keys - bin coded distance between centers in the molecule.
- Hydrogen bond donor
- Hydrogen bond acceptor
- Postitive charge center
- Ring center
ChemLib routines
ChemLib is a set of library routines that allow the user access to the Chem-X graphics routines and the Chem-X data structures. It allows the user to write custom routines to manipulate Chem-X data. Full details of ChemLib can be found in the ChemLib Programming Guide. At the NCI we have written ChemLib routines to handle:- Counting chiral centers in a database.
- Writing the 3D Keys to an ASCII file.