Quantum-Chemical Descriptors in QSAR/QSPR Studies

TL;DR: Applications of quantum chemical descriptors in the development of QSAR/QSPR dealing with the chemical, physical, biochemical, and pharmacological properties of compounds are reviewed.

Abstract: Quantitative structure-activity and structureproperty relationship (QSAR/QSPR) studies are unquestionably of great importance in modern chemistry and biochemistry. The concept of QSAR/QSPR is to transform searches for compounds with desired properties using chemical intuition and experience into a mathematically quantified and computerized form. Once a correlation between structure and activity/property is found, any number of compounds, including those not yet synthesized, can be readily screened on the computer in order to select structures with the properties desired. It is then possible to select the most promising compounds to synthesize and test in the laboratory. Thus, the QSAR/QSPR approach conserves resources and accelerates the process of development of new molecules for use as drugs, materials, additives, or for any other purpose. While it is not easy to find successful structureactivity/property correlations, the recent exponential growth in the number of papers dealing with QSAR/ QSPR studies clearly demonstrates the rapid progress in this area. To obtain a significant correlation, it is crucial that appropriate descriptors be employed, whether they are theoretical, empirical, or derived from readily available experimental characteristics of the structures. Many descriptors reflect simple molecular properties and thus can provide insight into the physicochemical nature of the activity/ property under consideration. Recent progress in computational hardware and the development of efficient algorithms has assisted the routine development of molecular quantummechanical calculations. New semiempirical methods supply realistic quantum-chemical molecular quantities in a relatively short computational time frame. Quantum chemical calculations are thus an attractive source of new molecular descriptors, which can, in principle, express all of the electronic and geometric properties of molecules and their interactions. Indeed, many recent QSAR/QSPR studies have employed quantum chemical descriptors alone or in combination with conventional descriptors. Quantum chemistry provides a more accurate and detailed description of electronic effects than empirical methods.1 Quantum chemical methods can be applied to quantitative structure-activity relationships by direct derivation of electronic descriptors from the molecular wave function. In many cases it has been established that errors due to the approximate nature of quantum-chemical methods and the neglect of the solvation effects are largely transferable within structurally related series; thus, relative values of calculated descriptors can be meaningful even though their absolute values are not directly applicable.2 Moreover, electronic descriptors derived from the molecular wave function can be also partitioned on the basis of atoms or groups, allowing the description of various molecular regions separately. Most work employing quantum chemical descriptors has been carried out in the field of QSAR rather than QSPR, i.e. the descriptors have been correlated with biological activities such as enzyme inhibition activity, hallucinogenic activity, etc.3-6 In part this has been because, historically, the search for quantitative relationships with chemical structure started with the development of theoretical drug design methods. Quantum-chemical descriptors have also been reported to correlate the reactivity of organic compounds, octanol/water partition coefficients, chromatographic retention indices, and various physical properties of molecules.7-11 The present article reviews applications of quantum chemical descriptors in the development of QSAR/QSPR dealing with the chemical, physical, biochemical, and pharmacological properties of compounds.