Quantum chemical molecular descriptors QSARs

Quantum-chemical molecular descriptors have been actively used in the quantitative structure-activity relationship studies of biological activities [1,2,72]. In the following, examples of QSARs involving quantum-chemical descriptors and applied on the enzymatic reactivity, pharmacological activity, and toxicity of compounds are discussed. 

The quantum-chemical molecular descriptors have been widely used in the development of quantitative structure-activity relationships for various pharmacological activities of compounds. Again, most of the QSARs developed include the electrostatic and/or MO-related descriptors. 

Recent progress in computational hardware and the development of efficient algorithms have assisted the routine development of molecular quantum-mechanical calculations. New semiempirical methods calculate realistic quantum-chemical molecular quantities in a relatively short computational time frame. Quantum-chemical calculations are thus an attractive source for molecular descriptors that can express all of the electronic and geometric properties of molecules and their interactions. Quantum-chemical methods can be applied to QSARs by direct derivation of electronic descriptors from the molecular wave function. 

While there are reviews of the application of various quantum chemical parameters in QSARs (Karelson et al., 1996 Famini and Wilson, 2002), little attention has been paid so far to the dependence of descriptor values on the level of theory. This holds true in particular with respect to potential discrepancies between semiempirical and ab initio methods when calculating parameters such as frontier orbital energies and descriptors that characterize the molecular charge distribution. 

Joshi, R.K., Meister, Th., Scapozza, L. and Ha, T.-K. (1994). A New Quantum Chemical Approach in QSAR-Analysis. Parametrisation of Conformational Energies into Molecular Descriptors Jmn (Steric) and Jsn (Electronic). Arzneim.Forsch., 44,779-790. 

A new quantum chemical approach in QSAR-analysis. Parametrisation of conformational energies into molecular descriptors Jmn (steric) and Jsn (electronic). Arzneim. Forsch. (German), 44, 779-790. 

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]. 

Three classes of calculated molecular descriptors, viz., topological and substruc-tural descriptors, geometrical (3-D) indices, and quantum chemical (QC) indices, have been extensively used in QSAR studies pertaining to drug discovery and environmental toxicology [8-12],... 

Chemical reactivity and biological activity can be related to molecular structure and physicochemical properties. QSAR models can be established among hydrophobic-lipophilic, electronic, and steric properties, between quantum-mechanics-related parameters and toxicity and between environmental fate parameters such as sorption and tendency for bioaccumulation. The main objective of a QSAR study is to develop quantitative relationships between given properties of a set of chemicals and their molecular descriptors. To develop a valid QSAR model, the following steps are essential ... 

Quantum chemistry is the foundation of molecular chemistry dealing with structure, properties, and interaction of molecules. The basic principles are offered by quantum mechanics. Quantum-chemical calculations are able to supply information needed for molecular descriptors for QSAR analyses. The use of quantum-chemical calculations is becoming common to establish molecular equilibrium geometries and conformations and to supply quantitative thermochemical and kinetic data. 

Many software packages have been developed for calculation of molecular descriptors. Table 5.5 shows some software employed for molecular modeling, quantum-chemical calculations, molecular dynamics, and QSARs. 

QSARs for hydrolysis are very limited for complex organic molecules. This is due to the difficulty of obtaining adequate molecular descriptors. The use of quantum-chemical... 

The primary supposition of any toxicological QSAR is that the potency of a compound is dependent upon its molecular structure, which is typically quantified by chemical properties (Schultz et al., 2002). Chemical descriptors include a variety of types, including atom, substituent, and molecular parameters. The most transparent of these are the molecular-based empirical and quantum chemical descriptors. Empirical descriptors are measured descriptors and include physicochemical properties such as hydrophobicity (Dearden, 1990). Quantum chemical properties are theoretical descriptors and include charge and energy values (Karelson et al., 1996). Physicochemical and quantum chemical descriptors are for the most part easily interpretable with regard to how that property may be related to toxicity. The classic example of this, the partitioning of a toxicant between aqueous and lipid phases, has been used as a measure of hydrophobicity for over a century (Livingstone, 2000). 

Derivation of kinetic rate constants for chemicals or congeners outside of the training set, but within the chemical class, is possible through QSAR and molecular modeling calculations based on appropriate descriptors (e.g., physicochemical and quantum chemical properties of the chemicals, as well as enzyme active site conformation). 

In our contribution we have focused the discussion on descriptors. The understanding of descriptors is essential for transparency of models and can also lead to mechanistic interpretation of models. Several questions are associated with descriptors. First of all, nowadays thousand of descriptors are defined and can be easily calculated with available software and the first question is how to the select the most relevant descriptors. The topological descriptors are sometimes promising, but there is no clear physicochemical interpretation for them. 3D molecular structure is a problematic quantity as it depends on the media where the molecule is, or on the method of determination. Quantum chemical descriptors, which have a clear physicochemical interpretation, are difficult to calculated. In the cases studies we have addressed some of those questions. We have discussed the sensitivity of the models, and particularly predictions, to descriptors used. According to the critical review of Snyder and Smith [87] on QSAR models for mutagenicity prediction a lot of work still remains to be done. 

Finally, three further studies on QSAR of artemisininoids applying a variety of quantum-chemical and conventional molecular descriptors [105], molecular quantum-similarity measures (MQSM, [111]) and topological descriptors based on molecular connectivity [112] have led to models of quite satisfactory statistical performance. However, apart from showing the applicability of the respective QSAR approaches to this type of compounds both studies offer comparatively little new information with respect to structure-activity relationships. 

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