Surface area, CoMFA

Nitrofiiranyl derivatives 95 CoMFA and CoMSIA Tested with a set of 15 molecules. CoMFA (R2 = 0.78) outperformed CoMSIA. c Log P and polar surface area or steric bulk did not improve the models Hevener et al. (43)... 

CoMFA and related 3D QSAR approaches have been applied to correlate various physicochemical properties. Equilibrium constants of the hydration of carbonyl groups could be explained by a combination of C=0 bond order, steric, and electrostatic fields [1005]. 3D QSAR studies that correlate a, inductive, and resonance parameters of benzoic acids [1015, 1016] as well as pKg values ofclonidine analogs [1017] show that a H " field precisely describes such electronic parameters, e.g. (Jm.p of benzoic acids (n = 49 rpir = 0.976 snr = 0.082 Spress = 0.093). Steric parameters of benzoic acids, like surface area and van der Waals volume can be described by a steric field alone, while values of acetic acid methyl esters need a combination of both steric and electrostatic fields (n = 21 rpix = 0.984 Sfit = 0.133 SpREss = 0.209) [1016]. 

Here S is the solvent-accessible surface area for atom /, a, is the hydrophobic atom constant for atom /, and R , = e, where r is the distance between atom i and grid point t. In addition to supplementing standard CoMFA fields, HINT has been demonstrated to effectively model experimentally determined log P values in cases where CLOGP values fail. A different fragment-based, distance-dependent method to estimate lipophilicity, the molecular lipophilic potential (MLP), has been recently shown to be useful in docking and as a third field in CoMFA studies. 

Because lipophilicity is so frequently correlated with potency in traditional QSAR applications, much attention has been paid to this property in CoMFA as well. Hydrophobic interactions are well described by an H2O molecular field computed by means of a combination of steric and hydrogen bond potential functions.9. i7o goth experimental octanol/water log P values and binding data also correlated with log P are well explained. These results are understood by recalling that log P is correlated with a combination of volume or surface area and hydrogen bonding ability. Because these individual properties are accounted by the steric and hydrogen bond or electrostatic potential functions, the hydrophobic effect is also accounted for. 

Two groups have developed hydrophobic fields for CoMFA 3D-QSAR applications. The HINT (hydrophobic interaction) program calculates the hydrophobic field of a molecule using Hansch-Leo hydrophobic constants scaled by surface area and a distance-dependent function. The MLP program... 

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