Rapid estimation of hydrophobicity for virtual combinatorial library analysis.
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abstract
Novel NPH (Nonpolar, Polar, Hydrogen) descriptors for rapid estimation of hydrophobicity, amenable for filtering extremely large virtual combinatorial libraries (VCL) are proposed, based on atom counts: P_at, the sum of polar atoms (sum of oxygen, nitrogen, phosphorus and sulfur); NP_at, the sum of non-polar atoms (the sum of carbons and halogens minus P_at); SHDA (the sum of hydrogen bond donors and acceptors). In combination with molecular weight, the following related parameters are defined: MWP_at (the "polar" molecular weight); MWNP_at (the "nonpolar" molecular weight); and MWSHDA (the "hydrogen bonding" molecular weight). The NPH descriptors provide moderate-to-good predictive PLS models when external prediction is evaluated against measured logP values (q2 pred > 0.5, n = 7954) or against calculated logP values (q2 pred > 0.6, n = 18 991). Related to hydrophobicity, the NPH descriptors are intended for fast analyses of extremely large VCLs (10(6)-10(12) compounds), even before the enumeration of reactants into products occurs.
