Molecular orbital QSARs

Aldose reductase (13) Ayerst Molecular orbital QSAR (1.8-2.3 A) Market... 

Hippurainen, K., Lotjonen, S., Laatikainen, R. and Vartiainen, T. (1992). Structural and Electronic Properties of MX Compounds Related to TAIOO Mutagenicity A Semiempirical Molecular Orbital QSAR Study. MuuRes., 266,181-188. 

Tuppurainen K, Lotjonen S, Laatikainen R, Vartiainen T. Structural and electronic properties of MX compounds related to TA100 mutagenicity a semiempirical molecular orbital QSAR study. Mutat Res 1992 266 181-188. 

Dearden,. C., Ghafourian, T. Hydrogen bonding parameters for QSAR comparison of indicator variables, hydrogen bond counts, molecular orbital and other parameters. J. Chem. Inf. Comput. Sci. 1999, 39, 231-235. 

The SPARC (Sparc Performs Automated Reasoning in Chemistry) approach was introduced in the 1990s by Karickhoff, Carreira, Hilal and their colleagues [16-18]. This method uses LSER [19] to estimate perturbed molecular orbitals [20] to describe quantum effects such as charge distribuhon and delocalizahon, and polarizability of molecules followed by quanhtative structure-activity relationship (QSAR) studies to correlate structure with molecular properties. SPARC describes Gibbs energy of a given process (e.g. solvation in water) as a sum of ... 

QSAR methods can be divided into several categories dependent on the nature of descriptors chosen. In classical one-dimensional (ID) and two-dimensional (2D) QSAR analyses, scalar, indicator, or topological variables are examples of descriptors used to explain differences in the dependent variables. 3D-QSAR involves the usage of descriptors dependent on the configuration, conformation, and shape of the molecules under consideration. These descriptors can range from volume or surface descriptors to HOMO (highest occupied molecular orbital) and LUMO (lowest unoccupied molecular orbital) energy values obtained from quantum mechanics (QM) calculations. 

Some of the earliest QSAR studies on CYPs were performed by Basak (257), Murray (258), and Marshall (205). Gao et al. (259) explored the influence of electronic parameters of CYP substrates in 1996. The findings of Basak that electronic terms would cancel out have been proven wrong by many research papers published in the following decades. Tyrakowska et al. (260) indicated via QSARs based on calculated molecular orbital descriptors that the cat (maximum velocity converted per nmol of P450 per min) for CYP catalyzed C4-hydroxylation rates of aniline derivatives of different species (rats, rabbit, mice, and human) are closely related to the highest occupied molecular orbital energy (EHOMo)> r - 0-97. Several reviews published by Lewis et al. (212,216,228,261-265) and Ekins (240) should also be mentioned. 

Lewis, D. F., Lake, B. G., and Parke, D. V. (1995) Molecular orbital-generated QSARs in a homologous series of alkoxyresorufins and studies of their interactive docking with P450s. Xenobiotica 25, 1355-1369. 

In this context, interesting exhaustive QSAR studies dealing with the assessment of phototoxic hazards of PAHs to aquatic organisms such as Daphnia were published some years ago [12-14]. Authors chose a descriptor based on the energy difference between the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO). They proposed that aromatic chemicals with a HOMO-LUMO gap energy in a window of 7.2 eV 0.4 eV have a high phototoxic potential. 

Molecular orbital theory provides electronic, as well as conformational, data for inclusion in QSAR development. 

The second variant of QSAR is the use of actual structural descriptors, such as molecular orbital indices or topological codes, to define numerically the structure of a molecule and to find linear relationships with numerical biological data (Kier and Hall, 1976, 1992). 

In recent years, molecular descriptors such as the energy of the highest occupied molecular orbital (EHomo) ar d the energy of the lowest unoccupied molecular orbital ( IUMO) have gained in popularity for QSAR analysis, as these descriptors are readily calculated from PC-based software such as SPARTAN. Before we discuss EHomo ar d ELumo further, a brief discussion of quantum chemistry is necessary. 

Parameters tested for the correlations were bond orders, atomic charges and lowest unoccupied molecular orbital (LUMO) parameters. Of the 12 sulfonylureas, a QSAR was developed for six of the compounds that hydrolyze exclusively at the sulfonylurea bridge. Equation (31) gives the best correlation for this group of compounds ... 

Commonly used descriptor variables for QSARs involving redox reactions include substituent constants (o), ionization potential, electron affinity, energy of the highest occupied molecular orbital (EHOMO)or lowest unoccupied molecular orbital (ELUMO), one-electron reduction or oxidation potential (E1), and half-wave potential (E1/2)- One descriptor variable (D), fit to a log-linear model, is usually sufficient to describe a redox property of P. Such a QSAR will have the form... 

Other chemical descriptors have been used to model other properties, or to improve the QSAR models with log P. The attempt has been to avoid the errors of the QSAR models. Indeed, some chemicals were not correctly modeled, and other descriptors have been introduced, producing multilinear relationships. The theoretical assumptions were modeled keeping into account other physico-chemical parameters, such as chemical reactivity, through chemical descriptors, such as the energy of the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO). 

Lewis, D.F.V., Molecular orbital calculations on tumor-inhibitory aniline mustards QSARs, Xenobiotica, 19, 243-251, 1989. 

Debnath, A.K., de Compadre, R.L.L., and Hansch, C., Mutagenicity of quinolines in Salmonella typhimurium TA100 a QSAR study based on hydrophobicity and molecular orbital determinants, Mutation Res., 280, 55-65, 1992c. 

Like toxicity assessments, descriptor values used in QSARs are also subject to variability. This fact is sometimes unnoticed, especially when values for descriptors are produced by software packages (Benfenati et al., 2001). In a study of the molecular orbital properties of pyridines, Seward... 

Most aquatic oxidation reactions are attributable to well-defined chemical oxidants. As a result, model systems can be designed where second-order rate constants can be determined precisely for families of organic congeners. The comparatively high quality of these data allows mechanistic models of electron transfer to describe aquatic oxidations of environmental interest. Kinetic studies of these processes have produced many QSARs, mostly simple empirical correlations with common convenient descriptors such as the Hammett constant (a), half-wave oxidation potential ( j/2)> energies of the highest occupied molecular orbital ( HOMO), or rate constants for other oxidation reactions as descriptors (Canonica and Tratnyek, 2003). Their predictive power has lead to engineering applications in water treatment and remediation. 

D. F. V. Lewis, Prog. Drug Metab., 12, 205 (1990). MO-QSARs A Review of Molecular Orbital-Generated Quantitative Structure-Activity Relationships. 

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