Rapid Estimation of Hydrophobicity for Virtual Combinatorial Library Analysis

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=18991). Related to hydrophobicity, the NPH descriptors are intended for fast analyses of extremely large VCLs (10⁶−10¹² compounds), even before the enumeration of reactants into products occurs.

Key Words:

• Combinatorial chemistry
• Computer chemistry
• Hydrophobicity
• Library profiling
• PLS
• Virtual screening