Quantum descriptors

ADMET Predictor Constitutional, functional group counts, topological, E-state, Moriguchi descriptors, Meylan flags, molecular patterns, electronic properties, 3D descriptors, hydrogen bonding, acid-base ionization, empirical estimates of quantum descriptors 297... 

Khandogin J, DM York (2004) Quantum descriptors for biological macromolecules from linear-scaling electronic structure methods. Proteins 56 (4) 724-737... 

The first derivatives of the molecular valency index were also proposed as quantum descriptors [Balawender, Komorowski et al., 1998], where the left-hand-side derivative describes the effect of the electrophilic attack and the right-hand-side derivative measures reactivity toward a nucleophilic attack. This last one is also related to the aromatic character of a molecule, measured by the —> diamagnetic susceptibility exaltation. 

Griinheidt Borges, E. and Takahata, Y. (2002) The 4-indolyl-2-guanidinothiazoles QSAR study of antiulcer activity using quantum descriptors. J. Mol. Struct. (Theochem), 580, 263-270. 

New nodal angle quantum descriptors - the Frontier Orbital Phase Angles - suggested by Clare (Clare, 1998) which considered as novel QSAR descriptors for benzene derivatives will be discussed in the application part. 

Nodal angle quantum descriptors and flip regression... 

Molecular dipole moments are often used as descriptors in QPSR models. They are calculated reliably by most quantum mechanical techniques, not least because they are part of the parameterization data for semi-empirical MO techniques. Higher multipole moments are especially easily available from semi-empirical calculations using the natural atomic orbital-point charge (NAO-PC) technique [40], but can also be calculated rehably using ab-initio or DFT methods. They have been used for some QSPR models. 

The molecular electronic polarizability is one of the most important descriptors used in QSPR models. Paradoxically, although it is an electronic property, it is often easier to calculate the polarizability by an additive method (see Section 7.1) than quantum mechanically. Ah-initio and DFT methods need very large basis sets before they give accurate polarizabilities. Accurate molecular polarizabilities are available from semi-empirical MO calculations very easily using a modified version of a simple variational technique proposed by Rivail and co-workers [41]. The molecular electronic polarizability correlates quite strongly with the molecular volume, although there are many cases where both descriptors are useful in QSPR models. 

The MEP at the molecular surface has been used for many QSAR and QSPR applications. Quantum mechanically calculated MEPs are more detailed and accurate at the important areas of the surface than those derived from net atomic charges and are therefore usually preferable [Ij. However, any of the techniques based on MEPs calculated from net atomic charges can be used for full quantum mechanical calculations, and vice versa. The best-known descriptors based on the statistics of the MEP at the molecular surface are those introduced by Murray and Politzer [44]. These were originally formulated for DFT calculations using an isodensity surface. They have also been used very extensively with semi-empirical MO techniques and solvent-accessible surfaces [1, 2]. The charged polar surface area (CPSA) descriptors proposed by Stanton and Jurs [45] are also based on charges derived from semi-empirical MO calculations. 

Quantum chemical descriptors such as atomic charges, HOMO and LUMO energies, HOMO and LUMO orbital energy differences, atom-atom polarizabilities, super-delocalizabilities, molecular polarizabilities, dipole moments, and energies sucb as the beat of formation, ionization potential, electron affinity, and energy of protonation are applicable in QSAR/QSPR studies. A review is given by Karelson et al. [45]. 

CODESSA (calculation of a series of difFerent descriptors including quantum chemical descriptors) Semichem Inc. - 7204 Mullen, Shawnee, KS 66216, USA http //www.semichem.com... 

Descriptors have to be found representing the structural features which are related to the target property. This is the most important step in QSPR, and the development of powerful descriptors is of central interest in this field. Descriptors can range from simple atom- or functional group counts to quantum chemical descriptors. They can be derived on the basis of the connectivity (topological or... 

Breindl et. al. published a model based on semi-empirical quantum mechanical descriptors and back-propagation neural networks [14]. The training data set consisted of 1085 compounds, and 36 descriptors were derived from AMI and PM3 calculations describing electronic and spatial effects. The best results with a standard deviation of 0.41 were obtained with the AMl-based descriptors and a net architecture 16-25-1, corresponding to 451 adjustable parameters and a ratio of 2.17 to the number of input data. For a test data set a standard deviation of 0.53 was reported, which is quite close to the training model. 

A descriptor for the 3D arrangement of atoms in a molceulc can be derived in a similar manner. The Cartesian coordinates of the atoms in a molecule can be calculated by semi-empirical quantum mechanical or molecular mechanics (force field) methods, For larger data sets, fast 3D structure generators are available that combine data- and rule-driven methods to calculate Cartesian coordinates from the connection table of a molecule (e.g., CORINA [10]). 

Quantum mechanical descriptors (e.g. HOMO-LUMO energy gap) 3D structure See Section 2.7.4... 

CODESSA can compute or import over 500 molecular descriptors. These can be categorized into constitutional, topological, geometric, electrostatic, quantum chemical, and thermodynamic descriptors. There are automated procedures that will omit missing or bad descriptors. Alternatively, the user can manually define any subset of structures or descriptors to be used. 

Sorich MJ, McKinnon RA, Miners JO, Winkler DA, Smith PA. Rapid prediction of chemical metabolism by human UDP-glucuronosyltransferase isoforms using quantum chemical descriptors derived with the electronegativity equalization method. J Med Chem 2004 47 5311-7. 

All of these parameters (with the possible exception of SAP) are frequently used in QSAR studies or as filters in virtual screening. The SAP descriptor was included to check for correlations between PSA and quantum chemically calculated charges. 

Two models of practical interest using quantum chemical parameters were developed by Clark et al. [26, 27]. Both studies were based on 1085 molecules and 36 descriptors calculated with the AMI method following structure optimization and electron density calculation. An initial set of descriptors was selected with a multiple linear regression model and further optimized by trial-and-error variation. The second study calculated a standard error of 0.56 for 1085 compounds and it also estimated the reliability of neural network prediction by analysis of the standard deviation error for an ensemble of 11 networks trained on different randomly selected subsets of the initial training set [27]. 

MolSurf parameters [33] are descriptors derived from quantum mechanical calculations. These descriptors are computed at a surface of constant electron density, with which a very fine description of the properties of a molecule at the Van der Waals surface can be obtained. They describe various electrostatic properties such as hydrogen-bonding strengths and polarizability, as well as Lewis base and acid strengths. MolSurf parameters are computed using the following protocol. 

Table 1 Calculation of some molecular-based descriptors for BOA, DIMBOA and MBOA. Physicochemical descriptor like logP (partition coefficient between octanol and water) constitutional descriptors like the number of a specified atoms or bonds (number of carbons, hydrogens, oxygens, nitrogens, single and aromatic bonds, the total number of atoms and bonds) and molecular weight quantum-mechanical descriptors like HOMO (Highest Occupied Molecular Orbital) and LUMO (Lowest Unoccupied Molecular Orbital).

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