Molecular biophilicity modeling of soluble small molecule properties in cell surface interaction and internalization

Abstract

Introduction: Biochemical interactions occur in vivo between small solubilizing molecules and intracellular membrane proteins due to differences in intermolecular affinity. Here, this relationship is further explored by in silico modeling of partitioning solvation parameters and proportion of molecular structure lipophilicity to hydrophilicity. Methods The partial bond length vdWV diameter (vdWDpb, nm) is applied for correlative modeling of diameter or volume normalized fractional solubility (Log S), partition coefficient (Log P). Method I (Sf) small molecules stratified as Tier I, Tier II or Tier III are multivariate modeled based on the degree of halogenated atom substitution. Method II (Sh) small molecules are modeled by subtractive hydrophilicity. Method III is developed for improved correlation of Log S to Log P for halogen heavy atom and multiple covalent bond-containing small molecules is developed as per: Log S = (Log P + a · Log PMW vdWD HAL or NON−HAL) · vdWDpb (fract, nm). The Linternal (or external) structure · Hpolar group −1 quotient is further normalized for alternating exterior methyln−1 group (CH2) biophilicity for determination of complex small molecule interaction at the cell surface. Results Method 1 Tier I, II and III MW-to-vdWDpb diameter correlative solubility for halogenate substituents is - Log S · vdWDpb − 1 (Da− 1 vol) = 1.020, 1.090 and 1.227 · (- Log S · vdWDpb− 1, nm− 1 vol) – B1, 2 or 3 (R2 = 0.9955, R2 = 0.9999, R2 = 0.9996). Method II-to-Log SPRED vdWVpb− 1 normalized correlative solubility is Log SVL · vdWVpb− 1 (nm− 1) = 2.7628 · (Log SCALC · vdWVpb− 1, nm− 1) − 0.4708 (R2 = 0.9895, r = 0.995). Method III MW vdWDpb-normalized molecules and vdWDpb normalized vdWDMW Da (0.01095 · RT)−1 relationship is 1.4863 (x) − 0.2615 (R2 = 0.992, r = − 0.995). Based on the L · Hpolar group−1, the interval range for cytosolic interaction at the periplasmic membrane is L · H− 1 > 0.057 < 0.093, and that for interaction with caveolin-associated protein is L · H− 1 0.093 < 0.297 (0.301) or with clathrin-AP is L · H− 1 0.301 ≤ (0.480) 0.497. Conclusions The fractional solubility-partition coefficient relationship is developed herein with partial bond length molecular diameter normalization and it is applicable to determination of small molecule solvation. The soluble small molecule structure-to-protein structure philicity relationship is determined to be predictive in sub-typing of complex linear and heterocyclic molecule cell surface interactions. There is further applicability of the findings for QSAR modeling of small molecule channel or receptor interactions.