Substructure versus Whole‐molecule Approaches for Calculating Log P

Abstract

AbstractThe validity of log P calculations is checked for the substructure methods CLOGP, KOWWIN, and AB/logP and the whole‐molecule method SciLogP via experimental log P for 174 molecules, comprising 90 simple organics and 84 more complex drugs. Averaged absolute residual sums (AARS) give the following ranking for the entire set: CLOGP>KOWWIN≈AB/logP>SciLogP. Separate analysis of simple organics yields: CLOGP>KOWWIN>AB/logP>SciLogP. For the drugs we find: CLOGP≈KOWWIN≈AB/LogP>SciLogP. In a second step, we compared the validity of the calculation programs focussing on structural factors with a critical impact on log P such as resonance and H‐bonding interactions. AARS values show that CLOGP and KOWWIN scored slightly better than AB/LogP and SciLogP; this agrees with the good performance of CLOGP and KOWWIN when dealing with simple compounds. AB/LogP averaged correction factors obtained from both simple and complex compounds, so it produced a slightly lower accuracy. α‐Effects, representing strong interactions between conjugated π‐electrons within polar functional groups, were identified from compounds lacking “isolating carbons”, which break α‐effects. All compounds in this data set are difficult to deal with for the substructure methods, but should be easy to deal with for the whole‐molecule approach. In practice, however, SciLogP performed worse than the substructure methods. The best performance was shown by CLOGP, followed by KOWWIN and AB/LogP. Taken together, all substructure methods produced better results than the whole‐molecule method. The possible explanation may be that substructure methods automatically account for unknown effects by splitting compounds into fragments and/or conducting class‐specific analyses. Whole‐molecule approaches cannot account for unknown effects, as long as they neglect class‐specific analyses. Among the substructure approaches, our results correlate with the methodology of algorithm development. CLOGP and KOWWIN were developed in a long iterative process, using simple organics for increment derivation and complex drugs for algorithm refinement. AB/LogP was developed in a fast two‐step procedure that did not discriminate between simple and complex compounds. So it produced slightly lower accuracy for simple organics, but not lower accuracy for the complex drugs.