No abstract

The 'quality' of small-molecule drug candidates, encompassing aspects including their potency, selectivity and ADMET (absorption, distribution, metabolism, excretion and toxicity) characteristics, is a key factor influencing the chances of success in clinical trials. Importantly, such characteristics are under the control of chemists during the identification and optimization of lead compounds. Here, we discuss the application of computational methods, particularly quantitative structure-activity relationships (QSARs), in guiding the selection of higher-quality drug candidates, as well as cultural factors that may have affected their use and impact.

O−H bond dissociation energies (BDEs) of phenol, p-aminophenol, and p-nitrophenol have been computed using ab initio and density functional theory (DFT) methods. The MP2 and MP4 methods consistently overestimate the absolute BDEs but provide reasonable relative BDEs. Spin projected MP2 and MP4 energies are not able to reproduce the substituent effects on the BDE. The BLYP and B3LYP DFT methods provide more reliable and economical approaches for prediction of phenol BDEs. B3LYP/6-31G** computed ΔBDEs for 10 substituted phenols have been compared with values determined by different experimental approaches. The computed values are in most cases within the uncertainty of the measurements. It is shown that the substituent effects on the BDEs can be interpreted in terms of polar and radical stabilization. The polar stabilization is found to be related to the ability of the substituent to delocalize the lone pair on the phenol oxygen. The radical stabilization is dependent on the degree of spin delocalization. A method for estimating relative polar and radical stabilization energies based on computed electrostatic potentials and spin densities is presented.

Using an ab initio self-consistent-field molecular orbital approach, we computed 3-21G//STO-3G* and STO-5G// STO-3G* electrostatic potentials and average local ionization energies for 17 para-substituted anilines. Our results demonstrate that the most negative potentials (V,,) and the local surface ionization energy minima (is.-) associated with the amine nitrogen lone pairs are highly sensitive indicators of the electron-donating and electron-attracting tendencies of the para substituents. We find excellent linear relationships between the 3-21G//STO-3G* amine nitrogen Vmi, and is.,;, and the a : Hammett constants of the substituent X; the correlation coefficients are 0.99. Correlations of sli htly lesser quality are shown to exist between Vmi., is.,,, and u,, up, and pK, Estimates of previously unknown u ! a n d pK, values are given. The presence of ring carbon meta to the substituent X also provides a predictive capability for determining u, values. Background the local minima (most negative values) of V(r) (1)(2)(3)(4)6 , 10, A continuing focus of our computational studies is the 13. 14, 24, 25) while the maxima of V(r) on the molecular interpretation and prediction of chemical reactive behavior surface serve the same Purpase for nucleophilic attack (6, 12-(1-7). We recently demonstrated that good correlations exist 14). between two calculated gaseous phase properties (the elecWe introduced another Propem, the average local trostatic potential V(r) and the average local ionization en-