(IUPAC Recommendations 1997)
> ALPHABETICAL ENTRIES
Prepared for publication by H. van de Waterbeemd1
(chairman), R.E. Carter2, G. Grassy3, H. Kubinyi4,
Y.C. Martin5, M.S. Tute6, P. Willett7
1 F. Hoffmann-La Roche Ltd., Pharma Research New Technologies,
CH-4070 Basel, Switzerland
2 Astra Hässle AB, Computational Chemistry, S-43183
Mölndal, Sweden
3 Centre de Biochimie Structurale, Faculté de Pharmacie,
F-34060 Montpellier, France
4 BASF AG, ZHB/W A30, D-67056 Ludwigshafen, Germany
5 Abbott Laboratories, Computer-Assisted Molecular Design,
Abbott Park IL 60064-3500, USA
6 University of Canterbury, Kent CT2 7NH, UK
7 University of Sheffield, Department of Information
Studies, Sheffield S10 2TN, UK
Membership of the Section during the period (1992-1995) when this report
was prepared was as follows:
President: J.G. Topliss (USA); Vice-president: N. Koga
(Japan); Past-president: C.G. Wermuth (France); Secretary:
W.D. Busse (Germany); Titular members: C.R. Ganellin (UK); L.A.
Mitscher (USA); Co-opted members: P. Anderson (USA); P.R. Andrews
(Australia); W.A. Denny (New Zealand); W. Granik (Russia); Y. Guindon
(Canada); C.A.G. Haasnoot (The Netherlands); J. Ide (Japan); R. Imhof
(Switzerland); P. Lindberg (Sweden); G. Tarzia (Italy); R.S. Xu (China);
National representatives: O.A.M. Stoppani (Argentina); E.J. Barreiro
(Brazil); A. Again (Bulgaria); J. Krepelka (Czechoslovakia); E.K. Pohjala
(Finland); A. Monge Vega (Spain).
Contributors
C.A.G. Haasnoot8, L.B. Kier9, K.
Müller1, S.V. Rose10, J. Weber11,
K.S. Wibley12, S. Wold13
8 Diosynth BV, PO box 20, NL-5340 BH Oss, The Netherlands
9 Virginia Commonwealth University, Department of Medicinal
Chemistry, Richmond, USA
10 BioFocus Molecular, Central Avenue, Chatham Maritime,
Chatham ME4 4TB, UK
11 Université de Genève, Departement de
Chimie Physique, CH-1211 Genève 4, Switzerland
12 University College London, Department of Chemistry,
London WC1H 0AJ, UK
13 University of Umea, Department of Organic Chemistry,
Research Group for Chemometrics, S-90187 Umea, Sweden
Reviewers
D.B. Boyd14, D.E. Clark15, Chr.
de Haën16, N.D. Heindel17, P. Kratochvíl18,
B. Kutscher19, R.A. Lewis20, M. Mabilia21,
W.V. Metanomski22, E.E. Polymeropoulos19, J.P.
Tollenaere23, M.D. Turnbull24, W.E. van der Linden25,
E.J. Van Lenten26
14Indiana University-Purdue University at Indianapolis,
Department of Chemistry, 402 North Blackford Street, Indianapolis,
Indiana 46202-3274, USA.
15Proteus Molecular Design Ltd., Proteus House, Lyme Green
Business Park, Macclesfield, Cheshire SK11 0JL, UK.
16Bracco spa, Via Egidio Folli 50, I-20134 Milano, Italy.
17Lehigh University, Department of Chemistry, Bethlehem,
Pennsylvania 18015-3172, USA.
18Academy of Sciences of the Czech Republic, Institute
of Macromolecular Chemistry, CZ-16206 Prague 6, Czech Republic.
19Asta Medica AG, Weismüllerstrasse 45, D-60314 Frankfurt
am Main, Germany
20Rhône-Poulenc Rorer, Dagenham Research Centre,
Rainham Road South, Dagenham, Essex RM10 7XS, UK
21Via Salvemini 9, I-36100 Vicenza, Italy
22CAS, P.O.Box 3012, Columbus, Ohio 4310-0012, USA
23Janssen Research Foundation, Turnhoutseweg 30, B-2340
Beerse, Belgium
24Zeneca Agrochemicals, Jealott's Hill Research Station,
Bracknell, Berkshire RG42 6EZ, UK
25University of Twente, The Netherlands
26American Chemical Society Committe on Nomenclature,
National Library of Medicine, Index Section Biobliographic Services,
1105 Cedrus Way, Rockville, MD 20854, USA
Abstract: Computational drug design is a rapidly growing field
which is now a very important component in the discipline of medicinal
chemistry. At the same time many medicinal chemists lack significant
formal training in this field and may not have a clear understanding
of some of the terminology used but need to grasp concepts, follow research
results, define problems for, and utilize findings of computational
drug design. In this context the IUPAC Medicinal Chemistry Section Committee
felt it would be useful to develop a glossary of terms used in computational
drug design for easy reference purposes. Also there is the possibility
that indifferent countries certain terms may not have the same meaning
and in such a case there would be value in trying to establish an international
definition standard. Accordingly a Working Party of seven experts in
the filed was assembled who constructed a glossary of some 100 terms.
Concise but sufficiently explanatory definitions have been formulated
based on a variety of literature sources and selected key references
provided.
ALPHABETICAL ENTRIES
Some of the definitions also appear in the Glossary of Terms used in
Medicinal Chemistry (IUPAC recommendations 1996; � 1996 IUPAC). These
are marked with an asterisk.
For some definitions the more extended form taken from the Glossary
of Terms in Theoretical Organic Chemistry (IUPAC recommendations 199*;
� 199* IUPAC) is included in smaller font.
[A] [B] [C]
[D] [E] [F] [G]
[H] [I-K] [L] [M]
[N] [O] [P] [Q]
[R] [S] [T] [U]
[V-Z]
Ab initio calculations
Ab initio calculations are quantum chemical calculations using
exact equations with no approximations which involve the whole electronic
population of the molecule.
Ab initio quantum mechanical methods (Synonymous with
non-empirical quantum mechanical methods) - Methods of quantum mechanical
calculations independent of any experiment other than the determination
of fundamental constants. The methods are based on the use of the full
Schrödinger equation to treat all the electrons of a chemical system.
In practice, approximations are necessary to restrict the complexity
of the electronic wavefunction and to make its calculation possible.
AM1 calculations
AM1 calculations are semi-empirical molecular orbital calculations developed
at the University of Austin in Texas (AM1 = Austin Model 1).
These calculations involve the valence electrons of the atoms of the
molecule. They are a further development of MNDO calculations (Wylie,
1994).
> MNDO calculations
AMBER
AMBER is a well-known molecular mechanics program for calculations on
proteins and nucleic acids.
> Molecular mechanics
Artificial neural networks
Artificial neural networks (ANN) are algorithms simulating the
functioning of human neurons and may be used for pattern recognition
problems, e.g., to establish quantitative structure-activity relationships.
Atomic orbitals (AO)
Atomic orbitals are mathematical functions (e.g., Gaussian, or Slater
functions) used in quantum chemical calculations. A set of atomic orbitals
described by a defined function is the basis set of atomic orbitals.
> Slater-type orbitals
Orbital (Atomic or Molecular) - A wavefunction which depends
explicitly on the spatial coordinates of only one electron.
> Alphabetical entries
Basis set
A basis set is a set of mathematical functions used in molecular orbital
(MO) calculations, e.g., the 6-31G* basis set used in
ab initio calculations. 6-31G* and similar expression refers to the
type of mathematical function used.
> Molecular orbital (MO) calculations
Basis set - A set of basis functions employed for the representation
of molecular orbitals. One may distinguish the minimal basis set (includes
one basis function for each SCF (SCF = Self-Consistent Field)
occupied atomic orbital with distinct principal and angular momentum
quantum numbers); split valence basis set (includes two or more sizes
of basis function for each valence orbital); double zeta (DZ) basis
set (a split valence basis set that includes exactly twice as many functions
as the minimal basis set; extended basis set (the set larger than the
double zeta basis set); polarized basis set (incorporates basis functions
of higher angular quantum number beyond what is required by the atom
in its electron ground state; allows orbitals to change not only size,
but also shape); basis set with diffuse functions and others.
> Alphabetical entries
Chemometrics
Chemometrics is the application of statistics to the analysis of
chemical data (from organic, analytical or medicinal chemistry) and
design of chemical experiments and simulations.
CLOGP values
CLOGP values are calculated 1-octanol/water partition coefficients,
frequently used in structure-property correlation or quantitative structure-activity
relationship (SPC/QSAR) studies (Leo, 1993)
> Structure-property correlations (SPC)
> Quantitative structure-activity relationships
(QSAR))
Cluster analysis
Cluster analysis is the clustering, or grouping, of large data sets
(e.g., chemical and/or pharmacological data sets) on the basis of similarity
criteria for appropriately scaled variables that represent the data
of interest. Similarity criteria (distance based, associative, correlative,
probabilistic) among the several clusters facilitate the recognition
of patterns and reveal otherwise hidden structures (Rouvray,
1990; Willett, 1987, 1991).
CNDO/2 calculations
CNDO/2 calculations are semi-empirical molecular orbital (MO)
calculations using complete neglect of differential overlap.
> Molecular orbital (MO) calculations
Comparative molecular field analysis (CoMFA)*
Comparative Molecular Field Analysis (CoMFA) is a 3D-QSAR method that
uses statistical correlation techniques for the analysis of the quantitative
relationship between the biological activity of a set of compounds with
a specified alignment, and their three-dimensional electronic and steric
properties. Other properties, such as hydrophobicity and H-bonding can
also be incorporated into the analysis (Cramer et
al., 1988; Kubinyi, 1993b).
> 3DQSAR
> Hydrophobicity
Computational chemistry*
Computational chemistry is a discipline using mathematical methods for
the calculation of molecular properties or for the simulation of molecular
behaviour. It also includes, e.g., synthesis planning, database searching,
combinatorial library manipulation (Hopfinger,
1981; Ugi et al., 1990).
Computer-assisted drug design (CADD)*
Computer-assisted drug design involves all computer-assisted techniques
used to discover, design and optimize biologically active compounds
with a putative use as drugs.
> Drug design
Computer-assisted molecular design (CAMD)
Computer-assisted molecular design involves all computer-assisted techniques
used to discover, design and optimize compounds with desired structure
and properties.
Computer-assisted molecular modeling (CAMM)
Computer-assisted molecular modeling is the investigation of molecular
structures and properties using computational chemistry and graphical
visualization techniques.
Computer chemistry
Computer chemistry is often used as equivalent to computational chemistry,
and can also refer to the use of computers in synthesis planning (Ugi
et al., 1990; Boyd, 1990).
Conformational analysis
Conformational analysis consists of the exploration of energetically
favorable spatial arrange-ments (shapes) of a molecule (conformations)
using molecular mechanics, molecular dynamics, quantum chemical calculations
or analysis of experimentally-determined structural data, e.g., NMR
or crystal structures.
Molecular mechanics and quantum chemical methods are employed to compute
conformational energies, whereas systematic and random searches, Monte
Carlo, molecular dynamics, and distance geometry are methods (often
combined with energy minimization procedures) used to explore the conformational
space.
> Distance geometry
> Molecular dynamics
> Molecular Mechanics
> Monte Carlo technique
> Quantum chemical methods
Conformationally flexible searching (CFS)
Conformationally flexible searching is a three dimensional-structure
database search taking into account the flexibility of molecules.
Connolly surface
The Connolly surface is the envelope traced out by the point of contact
of a defined probe (e.g., a sphere) and a molecule of interest where
they touch once, plus the van der Waals surface of the probe where it
touches twice or more (the re-entrant surface), It is used to visualize
the molecular surface.
Craig plot
A Craig plot is a plot of two substituent parameters (e.g., Hansch-Fujita
p and Hammett s values) used in analog design.
CSSR
The CSSR (Crystal Structure Search Retrieval) file format is
one of several used by the Cambridge Crystal Structure Database (CSD)
to store molecular structures. This format is used in many molecular
modeling software packages.
> Alphabetical entries
De novo design*
De novo design is the design of bioactive compounds by the
incremental construction of a ligand model within the receptor or enzyme
active site, the structure of which is known from X-ray or nuclear magnetic
resonance (NMR) data.
Discriminant analysis
Discriminant analysis is a statistical technique to find a set of descriptors
which can be used to detect and rationalize separation between activity
classes.
Distance geometry
Distance geometry is a mathematical method used to build three-dimensional
(3D) molecular models from a set of approximate interatomic distances
(e.g., nuclear Overhauser effect (NOE) experiments in nuclear
magnetic resonance (NMR) suggest only ranges of distances). Distance
geometry can be used to define a 3D pharmacophore starting from a set
of molecules with the same mechanism of action, or for the generation
of likely geometries for drug-receptor complexes using intermolecular
distance constraints. (Crippen, 1988).
Docking studies
Docking studies are computational techniques for the exploration
of the possible binding modes of a substrate to a given receptor, enzyme
or other binding site.
D-optimal design
D-optimal design is an experimental design technique based on the optimization
of the determinant calculated from the variance-covariance matrix of
the descriptors. It is used to maximize the efficiency of fractional
(uncomplete) factorial design.
> Factorial design
> Fractional factorial design
3D-QSAR (three-dimensional quantitative structure-activity
relationships)*
Three-dimensional quantitative structure-activity relationships (3D-QSAR)
involves the analysis of the quantitative relationship between the biological
activity of a set of compounds and their three-dimensional properties
using statistical correlation methods.
Drug design
Drug design includes not only ligand design, but also pharmacokinetics
and toxicity, which are mostly beyond the possibilities of structure-
and/or computer-aided design. Nevertheless, appropriate chemometric
tools, including experimental design and multivariate statistics, can
be of value in the planning and evaluation of pharmacokinetic and toxicological
experiments and results. Drug design is most often used instead of the
correct term "Ligand Design”.
> Alphabetical entries
Electrostatic field and potential
The electrostatic field and potential are properties of a molecule
arising from the interaction between a charged probe, such as a positive
unit point charge reflecting a proton, and a target molecule. These
fields and potential are being used in three-dimensional quantitative
structure-activity relationship (3D-QSAR) studies and to compare
or assess the similarity of a set of molecules.
Electrostatic potential - A physical property
equal in magnitude to the electrostatic energy between the static charge
distribution, r(r), of an atomic or molecular system and a positive unit
point charge located at r. The electrostatic potential V(r) that is produced
at any point r by the electrons and nuclei (A) of the system is given
by i.e. V(r) = S ZA/|RA-r| - r(r')dr'/|r'-r|.
Energy minimization
Energy minimization is a mathematical procedure to locate the
stable conformations of a molecule (energy minima), as determined by
molecular mechanics or quantum mechanical calculations.
> Molecular mechanics
> Quantum chemical calculations
Experimental design
Experimental design is the use of mathematical and statistical methods
to select the minimum number of experiments or compounds for optimal
coverage of descriptor or variable space.
Extended Hückel (EH) calculations
Extended Hückel calculations are low-level semi-empirical molecular
orbital (MO) calculations.
Extended Hückel method - A semi-empirical all-valence electron
quantum mechanical method which uses the same approximations, apart
from p-approximation and neglect of overlap integrals, as those of Hückel
molecular orbital theory. The method reproduces relatively well the
shapes and the order of energy levels of molecular orbitals. The account
for overlap makes it possible to describe the net destabilization caused
by interaction of two double occupied orbitals.
Extrathermodynamic approach
The extrathermodynamic approach involves the correlation between
variables which, from a strictly thermodynamic standpoint, are not related.
It is the basis of Hansch analysis used in traditional QSAR (Kubinyi,
1993a)
> Alphabetical entries
Factorial design (FD)
Factorial design is an experimental design technique in which each variable
(factor or descriptor) is investigated at fixed levels. In a two-level
FD, each variable can take two values, e.g., high and low lipophilicity.
File format
The (molecular) file format describes the layout of a computer data
file. It is a set of instructions on how a molecule is encoded with
respect to its connectivity, atom types, coordinates, and may also contain
bibliographic data.
Force field
The force field is a set of functions and parametrization used in molecular
mechanics calculations.
Force field - Within the molecular mechanics approach, a set
of potential functions defining bond stretch, bond angle (both valence
and dihedral) distortion energy of a molecule as compared with its nonstrained
conformation (that characterized by standard values of bond lengths
and angles). A set of transferable empirical force constants is preassigned
and the harmonic approximation is usually employed. Some force fields
may contain terms for interactions between non-bonded atoms, electrostatic,
hydrogen bond and other structural effects as well as account for anharmonicity
effects.
In vibrational spectroscopy, the inverse problem is solved of determining
a set of force constants and other parameters of a choosen potential
energy functions which would match with experimentally observed vibrational
frequencies of a given series of congeneric molecules.
Fractional factorial design (FFD)
Fractional factorial design is an experimental design technique, using
a reduction factor in order to limit the number of experiments to a
lower number than obtained by factorial design.
Free energy perturbation calculations
Free energy perturbation calculations are mathematical procedures used
in molecular dynamics studies to gradually convert one chemical species
to another in a thermodynamic cycle.
Free-Wilson (FW) analysis
Free-Wilson analysis is a regression technique using the presence or
absence of substituents or groups as the only molecular descriptors
in correlations with biological activity (Kubinyi,
1993a).
> Alphabetical entries
Gaussian-type orbitals (GTO)
Gaussian-type orbitals are mathematical functions used in ab initio
calculations. They have superceded Slater-type orbitals because of the
greater computational efficiency that results.
> Slater-type orbitals
Genetic algorithm
A genetic algorithm is an optimization algorithm based on the mechanisms
of Darwinian evolution which uses random mutation, crossover and selection
procedures to breed better models or solutions from an originally random
starting population or sample (Rogers and Hopfinger,
1994).
GOLPE
Generating optimal linear PLS estimations. It is an advanced
variable selection technique in partial least squares (PLS) used
in three-dimensional quantitative structure-activity relationships (3D
QSAR) studies to handle very large data sets.
> Partial least squares (PLS)
GRID
GRID is a program for receptor/ligand mapping. It calculates interaction
energies between probes and target molecules at interaction points on
a 3D grid (Goodford, 1985).
> Alphabetical entries
Hamiltonian
The Hamiltonian is a mathematical operator function used in molecular
orbital calculations (Wylie, 1994).
Hammett constant s
The Hammett constant is an electronic substituent descriptor reflecting
the electron-donating or -accepting properties of a substituent (Hansch
et al., 1995).
Hansch analysis*
Hansch analysis is the investigation of the quantitative relationship
between the biological activity of a series of compounds and their physicochemical
substituent or global parameters representing hydrophobic, electronic,
steric and other effects using multiple regression correlation methodology
(Hansch and Fujita, 1964; Kubinyi,
1993a).
Hansch-Fujita p constant
The Hansch-Fujita p constant describes the
contribution of a substituent to the lipophilicity of a compound (Hansch
and Fujita, 1964).
Highest occupied molecular orbital (HOMO) energy
The highest occupied molecular orbital (HOMO) energy is obtained by
molecular orbital calculations and relates to the ionization potential
of a molecule and its reactivity as a nucleophile.
> Lowest unoccupied molecular orbital (LUMO) energy
Frontier orbital - The molecular orbitals that involve the highest
occupied molecular orbital (HOMO) and the lowest unoccupied molecular
orbital (LUMO) of a given molecular entity. In the case of an
odd-electron molecular entity, when its HOMO is occupied by a single
electron such a molecular orbital is termed a singly occupied molecular
orbital (SOMO). Depending on the properties of the reactive partner,
the SOMO of a given species may function as either HOMO or LUMO. The
special importance of the frontier orbitals is due to the fact that
a broad variety of chemical reactions takes place at a position and
in a direction where the overlap of HOMO and LUMO of the respective
reactants is maximal.
Homology model
A homology model is a model of a protein, whose
three-dimensional structure is unknown, built from, e.g., the X-ray
coordinate data of similar proteins or using alignment techniques and
homology arguments.
Hydrophilicity*
Hydrophilicity is the tendency of a molecule to be solvated by water.
Hydrophobic fragmental constant (f or f')
The hydrophobic fragmental constant of a substituent or molecular fragment
represents the lipophilicity contribution of that molecular
fragment (Rekker and De Kort, 1979; Hansch
and Leo, 1979; Rekker and Mannhold, 1992).
Hydrophobicity*
Hydrophobicity is the association of non-polar groups or molecules in
an aqueous environment which arises from the tendency of water to exclude
non-polar molecules (Martin, 1978; Martin
et al., 1989; Dean, 1990).
> Alphabetical entries
Indicator variable
An indicator variable is a descriptor that can assume only two values
indicating the presence (=1) or absence (=0) of a given condition. It
is often used to indicate the absence or presence of a substituent or
substructure. More broadly, it is a variable which can encode anything
that the investigator chooses.
> Alphabetical entries
Ligand design
Ligand design is the design of ligands using structural information
about the target to which they should bind, often by attempting to maximize
the energy of the interaction.
> Docking studies
Linear combination of atomic orbitals (LCAO)
The linear combination of atomic orbitals (LCAO) is a mathematical method
used in quantum chemical calculations. It expresses the approximation
of the molecular orbital function as a linear combination of atomic
orbitals chosen as the basis functions.
Lipophilicity*
Lipophilicity represents the affinity of a molecule or a moiety for
a lipophilic environment. It is commonly measured by its distribution
behaviour in a biphasic system, either liquid-liquid (e.g. partition
coefficient in 1-octanol/water) or solid-liquid (retention on reversed-phase
high-performance liquid chromatography (RP-HPLC) or thin-layer
chromatography (TLC) system).
Lowest unoccupied molecular orbital (LUMO) energy
The lowest unoccupied molecular orbital (LUMO) energy is obtained
from molecular orbital calculations and represents the electron affinity
of a molecule or its reactivity as an electrophile.
> Highest occupied molecular orbital (HOMO) energy
> Alphabetical entries
MINDO/3 calculations
MINDO/3 (Modified Intermediate Neglect of Differential Overlap)
calculations are semi-empirical MO calculations (Bingham
et al, 1975).
MM2 calculations
MM2 calculations involve molecular mechanical calculations using version
2 of the widely-distributed force field program MM2 (Allinger,
1977).
MNDO calculations
MNDO calculations are semi-empirical molecular orbital (MO) calculations,
using a modified neglect of diatomic (differential) overlap approximation.
MOL file format
The MOL file format is used to encode chemical structures,
substructures and conformations as text-based connection tables. It
is used by MDL Information Systems Inc. (e.g., in their MACCS or ISIS
programs) (Dalby et al., 1992).
Molar refractivity (MR)
The molar refractivity is the molar volume corrected by the refractive
index. It represents size and polarizability of a fragment or molecule.
Molecular connectivity index
A molecular connectivity index is a numeric descriptor derived from
molecular topology (Kier and Hall, 1976).
Molecular descriptors
Molecular descriptors are terms that characterize a specific aspect
of a molecule (Van de Waterbeemd and Testa,
1987).
Molecular design
Molecular design is the application of all techniques
leading to the discovery of new chemical entities with specific properties
required for the intended application.
Molecular dynamics
Molecular dynamics is a simulation procedure consisting of the computation
of the motion of atoms in a molecule or of individual atoms or molecules
in solids, liquids and gases, according to Newton's laws of motion.
The forces acting on the atoms, required to simulate their motions,
are generally calculated using molecular mechanics force fields.
> Molecular mechanics
Molecular electrostatic potentials (MEP)
Molecular electrostatic potentials (MEP) are electrostatic properties
of a molecule based on the charge density as calculated directly from
the molecular wavefunction. The electrostatic potential (scalar with
dimensions of energy) is calculated at a point in the vicinity of a
molecule. The spatial derivative is the electric force (vector) acting
on a unit positive charge at that point caused by the nuclei and the
electrons of the molecule (Williams, 1991).
Molecular graphics*
Molecular graphics is a technique for the visualization and manipulation
of molecules on a graphical display device.
Molecular interaction potentials (MIP)
Molecular interaction potentials (MIP) are field properties arising
from the interaction of a probe (e.g., methyl, proton or water) with
a molecule. These are calculated in a space around the molecule.
Molecular lipophilic potentials (MLP)
Molecular lipophilic potentials are properties on the Van der Waals
or solvent accessible molecular surface or any other point in space
(e.g., in a 3D grid for CoMFA studies) calculated from atomic lipophilicity
contributions. It can be used for log P calculations, CoMFA and docking
studies (Gaillard et al., 1994).
Molecular mechanics
Molecular mechanics is the calculation of molecular conformational geometries
and energies using a combination of empirical force fields (Burkert
and Allinger, 1982).
Molecular mechanics - (synonymous with force field method) -
Method of calculation of geometrical and energy characteristics of molecular
entities on the basis of empirical potential functions (see force field)
the form of which is taken from classical mechanics. The method implies
transferability of the potential functions within a network of similar
molecules. An assumption is made on "natural” bond lengths
and angles, deviations from which result in bond and angle strain respectively.
Repulsive or attractive van der Waals and electrostatic forces between
nonbonded atoms are also taken into account.
Molecular modeling*
Molecular modeling is the investigation of molecular structures and
properties using computational chemistry and graphical visualization
techniques in order to provide a plausible three-dimensional representation
under a given set of circumstances.
Molecular orbital (MO) calculations
Molecular orbital (MO) calculations are quantum chemical calculations
based on the Schrödinger equation, which can be subdivided into
semi-empirical and ab initio methods.
> Ab initio calculations
Molecular orbital theory - An approach to molecular quantum
mechanics which uses one-electron functions (orbitals) to approximate
the full wavefunction.
Molecular shape
The molecular shape is an attribute of a molecule dealing with spatial
extension, form, framework, or geometry. It is often described by, e.g.,
principal axes, ovality, or connectivity indices.
Molecular (dis-)similarity
Molecular (dis-)similarity is a number to express structural relatedness
between pairs of molecules, e.g., the so-called Carbo, Hodgkin or Tanimoto
coefficient (Good, 1992; Willett
and Winterman, 1986).
Molecular topology
Molecular topology is the description of the way in which the atoms
in a molecule are bonded together.
> Molecular connectivity
> Topological index
Molfile
A molfile is a table containing atom type, connectivity and a more or
less arbitrary 2D or 3D information about a molecule.
Well-known file formats include the MOLfile used by MDL Information
Systems Inc. (e.g., in the database MACCS), the MOL2 file used by Tripos
Associates (e.g., in the modeling package SYBYL), or the CSSR format.
Monte Carlo technique
The Monte Carlo technique is a simulation procedure consisting
of randomly sampling the conformational space of a molecule.
Mulliken population analysis
Mulliken population analysis is
a method for allocating electrons to atoms in order to generate partial
atomic charges. The results are strongly dependent on the basis set
used.
Mulliken population analysis - A partitioning scheme
based on the use of density and overlap matrices of allocating the electrons
of a molecular entity in some fractional manner among its various parts
(atoms, bonds, orbitals). As with other schemes of partitioning the
electron density in molecules, Mulliken population analysis is arbitrary
and strongly dependent on the particular basis set employed. However,
comparison of population analyses for a series of molecules is useful
for a quantitative description of intramolecular interactions, chemical
reactivity and structural regularities.
Multivariate statistics
Multivariate statistics is a set of statistical tools to analyze data
(e.g., chemical and biological) matrices using regression and/or pattern
recognition techniques.
> Alphabetical entries
Neural networks
> Artificial neural networks
Non-bonded energy terms
Non-bonded energy terms are potential energy functions describing van
der Waals, electrostatic and hydrogen bonding interactions in a force
field.
> Alphabetical entries
Parameter space
The parameter space is a multidimensional space spanned by the descriptors
in a data set.
Partial least squares (PLS)
Partial least squares projection to latent structures (PLS)
is a robust multivariate generalized regression method using projections
to summarize multitudes of potentially collinear variables (Wold
et al., 1993).
Pattern recognition*
Pattern recognition is the identification of patterns in large data
sets, using appropriate mathematical methodology. Examples are principal
component analysis (PCA), SIMCA, partial least squares
(PLS) and artificial neural networks (ANN) (Rouvray,
1990; Van de Waterbeemd, 1995ab).
PCILO calculations
PCILO (Perturbative Configuration Interaction using Localized Orbitals)
calculations are semi-empirical molecular orbital calculations related
to CNDO/2 and MNDO calculations.
PDB
The Protein Data Bank (PDB) maintained at Brookhaven National
Library, Upton, New York, which contains X-ray structures of several
hundreds of proteins.
> PDB file
PDB file
A PDB (Protein Data Bank) file is an ASCII (American
Symbolic Code for Information Interexchange = text) file used to
store the atomic coordinates of a molecule, usually a protein or nucleic
acid.
> PDB
Pharmacophore generation
Pharmacophore generation is a procedure
to extract the most important common structural features relevant for
a given biological activity from a series of molecules with a similar
mechanism of action.
PM3
PM3 is a widely used semi-empirical molecular mechanics program.
> Molecular mechanics
Principal components analysis (PCA)
Principal components analysis is a data reduction method using mathematical
techniques to identify patterns in a data matrix. The main element of
this approach consists of the construction of a small set of new orthogonal,
i.e., non-correlated, variables derived from a linear combination of
the original variables.
Principal properties
Principal properties are scales of substituent or amino acid values
derived by principal components analysis from a large matrix of structure
descriptor variables, and useful in series design and data analysis.
> Alphabetical entries
Quantitative structure-activity relationships
(QSAR)*
Quantitative structure-activity relationships (QSAR) are mathematical
relationships linking chemical structure and pharmacological activity
in a quantitative manner for a series of compounds. Methods which can
be used in QSAR include various regression and pattern recognition techniques.
QSAR is often taken to be equivalent to chemometrics or multivariate
statistical data analysis. It is sometimes used in a more limited sense
as equivalent to Hansch analysis. QSAR is a subset of the more general
term SPC (Kubinyi, 1993a).
Quantum chemical calculations
Quantum chemical calculations are molecular property calculations based
on the Schrödinger equation, which take into account the interactions
between electrons in the molecule.
> Alphabetical entries
Receptor*
A receptor is a protein or a protein complex in or on a cell that specifically
recognizes and binds to a compound acting as a molecular messenger (neurotransmitter,
hormone, lymphokine, lectin, drug, etc). In a broader sense, the term
receptor is often used as a synonym for any specific (as opposed to
non-specific such as binding to plasma proteins) drug binding site,
also including nucleic acids such as DNA.
Receptor mapping*
Receptor mapping is the technique used to describe the geometric and/or
electronic features of a binding site when insufficient structural data
for this receptor or enzyme are available. Generally the active site
cavity is defined by comparing the superposition of active to that of
inactive molecules.
Regression analysis
Regression analysis is the use of statistical methods for modeling a
set of dependent variables, Y, in terms of combinations of predictors,
X. It includes methods such as multiple linear regression (MLR) and
partial least squares (PLS).
> Alphabetical entries
Semi-empirical methods
Semi-empirical methods are molecular orbital calculations using various
degrees of approximation and using only valence electrons.
Semi-empirical quantum mechanical methods - The methods which
use parameters derived from experimental data to simplify computations.
The simplification may occur at various levels: simplification of the
Hamiltonian (e.g. as in the Extended Hückel method), approximate
evaluation of certain molecular integrals (see, for example, zero differential
overlap), simplification of the wave function (for example, use of p
electron approximation as in Pariser-Parr-Pople).
Sequential simplex method
The sequential simplex method is an experimental design method used
for the rapid optimization of properties.
SIMCA
The SIMCA (SIMple Classification Analysis or Soft Independent Modeling
of Class Analogy) method is a pattern recognition and classification
technique (Dunn and Wold, 1995).
Simulated annealing
Simulated annealing is a procedure used in molecular dynamics
simulations, in which the system is allowed to equilibrate at high temperatures,
and then cooled down slowly to remove kinetic energy and to permit trajectories
to settle into local minimum energy conformations.
Slater-type orbitals (STO)
Slater-type orbitals are mathematical functions involving exponential
functions, used in ab initio quantum chemical calculations. These functions
mimic the electronic distribution in atoms and were used in ab initio
calculations, but have now been superceded by Gaussian-type orbitals.
> Gaussian-type orbitals
Slater type atomic orbital (STO) - The exponential function
on an atom; its radial dependence is given by Nrn-1 exp(-zr),
where n is the effective principal quantum number and z is the orbital
exponent (screening constant) derived from empirical considerations.
The angular dependence is usually introduced by multiplying the radial
one by a spherical harmonic Ylm(q,F).
SMILES
SMILES (Simplified Molecular Input Line Entry System) is a string notation
used to describe the nature and topology of molecular structures.
Solvent-accessible surface
The solvent-accessible surface is described as the surface traced out
by of a probe molecule, e.g., water, rolling over the van der Waals
surface of a molecule. There are two types: a) the surface formed by
the locii of the centre of a spherical probe rolled around a molecule
in the van der Waals contact and b) the contact surface (or Connolly/Richards
surface).
> Connolly surface
STO-3G basis set
A STO-3G basis set is a set of Gaussian-type orbitals (GTO),
each of which uses three Gaussian functions to approximate a Slater-type
orbital (STO). More extended modern basis sets include STO-3-21G
or STO-KG.
Structure-based design*
Structure-based design is a design strategy for new chemical entities
based on the three-dimensional (3D) structure of the target obtained
by X-ray or nuclear magnetic resonance (NMR) studies, or from
protein homology models.
Structure-property correlations (SPC) *
Structure-property correlations (SPC) refers to all statistical
mathematical methods used to correlate any molecular property (intrinsic,
chemical or biological) to any other property, using statistical regression
or pattern recognition techniques (Van
de Waterbeemd, 1992).
Swain-Lupton parameters (F and R)
The Swain and Lupton parameters (F and R) are electronic field
and resonance descriptors derived from Hammett constants (Hansch
and Leo, 1979).
> Alphabetical entries
Taft steric parameter (Es)
The Taft steric parameter is a relative reaction parameter encoding
the reaction rate retardation due to the size of a substituent group.
Three-dimensional database searching
Three-dimensional database
searching is a lead finding technique using three-dimensional structures
of compounds stored in a database.
Topliss tree*
A Topliss tree is an operational scheme for analog design (Topliss,
1972).
Topological index
A topological index is a numerical value associated with chemical constitution
for correlation of chemical structure with various physical properties,
chemical reactivity or biological activity.
> Molecular connectivity
Topological index - The numerical basis for topological indices
is provided (depending on how a molecular graph is converted into a
numerical value) by either the adjacency matrix or the topological distance
matrix. In the latter the topological distance between two vertices
is the number of edges in the shortest path between these.
> Alphabetical entries
United atom approach
The united atom approach is a simplification used by molecular mechanics
programs such as AMBER and CHARMM which approximates the influence of
groups of atoms or molecular fragments by treating them as single atoms.
> Alphabetical entries
Verloop STERIMOL parameters
The STERIMOL parameters defined by Verloop are a set of substituent
length and width parameters (Verloop, 1987).
Complementary and additional information may be found in the following
related documents:
- Glossary of Terms in Theoretical Organic Chemistry (V.I. Minkin)
- Guidelines for the Publication of Research Results from Empirical
Force Field
Calculations (D.J. Raber)
- Best Values of Substituent Constants (J. Shorter)
- Acronyms used in Theoretical Chemistry (R.D. Brown)
REFERENCES
Allinger, N.L., J. Amer. Chem. Soc.
99, 8127 (1977)
Bingham, R.C. et al., J. Amer. Chem. Soc.
97, 1285 (1975)
Boyd, D.B., Ed., Reviews in Computational Chemistry,
Vol. 1 (1990)
Burkert, U. and Allinger, N.L., Molecular Mechanics,
ACS Monograph 177 (1982)
Cammarata, A. and Menon, J.K., J. Med.
Chem. 19, 739 (1976)
Cramer III, R.D., Patterson, D.E. and Bunce,
J.D., J. Amer. Chem. Soc. 110, 5959 (1988)
Crippen, G.M. and Havel, T.F., Distance Geometry
and Molecular Conformation, Wiley, New York (1988)
Dalby, A., Nourse, J.G., Hounsell, W.D., Gushurst,
A.K.I., Grier, D.L., Leland, B.A., and Laufer, J. J. Chem. Inf. Comput.
Sci. 32, 244-255 (1992)
Dean, P.M., In: Concepts and Applications of Molecular
Similarity, Johnson, A.M. and Maggiora, G.M., Eds., Wiley, New York
(1990), pp 211-238
Dunn, W.J. and Wold, S. In: Chemometric Methods
in Molecular Design, Van de Waterbeemd, H., Ed., VCH, Weinheim (1995),
pp. 179-193.
Gaillard, P., Carrupt, P.A., Testa, B. and
Boudon, A., J. Comput. Aided Mol. Des. 8, 83-96 (1994)
Rogers, D. and Hopfinger, A.J., J. Chem.
Inf. Comp. Sci. 34, 854-866 (1994)
Good, A.C., J. Mol. Graph. 10, 144-151
(1992)
Goodford, P.J., J. Med. Chem. 28,
849 (1985)
Hansch, C. and Fujita, T., J. Amer. Chem.
Soc. 86, 1616-1626 (1964)
Hansch, C. and Leo, A., Substituent Constants
for Correlation Analysis in Chemistry and Biology, Wiley, New York (1979)
Hansch, C., Leo, A. and Hoekman, D., Exploring
QSAR, American Chemical Society, Washington (1995)
Hopfinger, A.J., J. Med. Chem. 24,
229 (1981)
Kier, L.B. and Hall, L.H., Molecular Connectivity
in Chemistry and Drug Research, Academic Press, London (1976)
Kubinyi, H., QSAR: Hansch Analysis and Related
Approaches (1993a), Vol. 1 of Methods and Principles in Medicinal Chemistry,
Mannhold, R. et al., Eds., VCH, Weinheim
Kubinyi, H., 3D-QSAR in Drug Design. Theory,
Methods and Applications (1993b). Escom, Leiden.
Leo, A.J., Chem.Revs. 93, 1281-1306
(1993)
Martin, Y.C., Quantitative Drug Design, Marcel
Dekker, New York (1978)
Martin, Y.C. et al., Modern Drug Research, Marcel
Dekker, New York (1989)
Rekker, R.F. and De Kort, H.M., Eur.J.Med.Chem.
14, 479-488 (1979)
Rekker, R.F. and Mannhold, R., Calculation of
Drug Lipophilicity, VCH, Weinheim (1992)
Rouvray, D.H., In: Concepts and Applications
of Molecular Similarity, Johnson, A.M. and Maggiora, G.M., Eds., Wiley,
New York (1990), pp 15-42.
Tollenaere, J.P., In: Guidebook on Molecular
Modeling in Drug Design (1995), Academic Press, London, pp. 337-356.
Topliss, J.G., J.Med.Chem. 15,
1006-1011 (1972)
Ugi, I., Wochner, M., Fontain, E., Bauer, J., Gruber,
B. and Karl, R., In: Concepts and Applications of Molecular Similarity,
Johnson, A.M. and Maggiora, G.M., Eds., Wiley, New York (1990), pp 239-288.
Van de Waterbeemd, H., Quant.Struct.-Act.Relat.
11, 200-204 (1992)
Van de Waterbeemd, H. and Testa, B.,
Adv. Drug Res. 16, 85-225 (1987)
Van
de Waterbeemd, H. (Ed.), Chemometric Methods in Molecular Design (1995a),
Vol. 2 of Methods and Principles in Medicinal Chemistry, Mannhold, R.
et al., Eds., VCH, Weinheim
Van de Waterbeemd, H. (Ed.), Advanced
Computer-Assisted Techniques in Drug Discovery (1995b), Vol.3 of Methods
and Principles in Medicinal Chemistry, Mannhold, R. et al., Eds., VCH,
Weinheim
Verloop, A., The STERIMOL Approach to Drug
Design, Marcel Dekker, New York (1987).
Willett, P., Similarity and Clustering in Chemical
Information Systems, John Wiley, New York (1987).
Willett, P. and Winterman, V., Quant. Struct
.-Act. Relat. 5, 18-25 (1986)
Willett, P., Three-dimensional Chemical Structure
Handling, John Wiley, New York (1991).
Williams, D.E., Rev. Comp. Chem. 2,
226 (1991).
Wold, S., Johansson, E. and Cocchi, M., In: 3D-QSAR
in Drug Design. Theory, Methods and Applications, Kubinyi, H., Ed.,
Escom, Leiden (1993), pp. 523-550.
Wylie, W.A., In: Molecular Modeling and Drug
Design, Vinter, J.G. and Gardner, M., Eds., Macmillan, London (1994).
World Wide Web version prepared by H.
van de Waterbeemd
