Three‐dimensional holograph vector of atomic interaction field (3D‐HoVAIF): a novel rotation–translation invariant 3D structure descriptor and its applications to peptides

Abstract

Quantitative structure-activity relationship (QSAR) study, important in drug design, mainly involves two aspects, molecular structural characterization (MSC) and construction of a statistical model. MSC focuses on transforming molecular structural and property characteristics into a group of numerical codes, dedicated to minimizing information loss during this process. In this context, common atoms in organic compounds are classified according to their families in the periodic table, and hybridization states, and on the basis of these, three nonbonding interactions (i.e. electrostatic, van der Waals and hydrophobic) are calculated, ultimately resulting in a new rotation-translation invariant, 3D-MSC, as a three-dimensional holograph vector of atomic interaction field (3D-HoVAIF). By applying 3D-HoVAIF to QSAR studies on two classical peptides including 58 angiotensin-converting enzyme (ACE) inhibitors and 48 bitter-tasting dipeptides, we get two excellent genetic algorithm-partial least squares (GA-PLS) models, with statistics r(2), q(2), root mean square error (RMSEE), and root mean square error of cross-validation (RMSCV) of 0.857, 0.811, 0.376, and 0.432 for ACE inhibitors and 0.940, 0.892, 0.153 and 0.205 for bitter-tasting dipeptides, respectively. By equally dividing the two datasets into training and test sets by D-optimal, the 3D-HoVAIF approach undergoes rigorous statistical validation. Furthermore, the superior performance of 3D-HoVAIF is confirmed in comparison with two other peptide MSC approaches referring to z-scale and ISA-ECI. For 58 ACE inhibitors, the GA-PLS model yields two principal components, with the following statistics: r(2) = 0.893, q(2) = 0.824, RMSEE = 0.349, RMSCV = 0.425, q2(ext) = 0.739, r2(ext)= 0.784, r2(0.ext) = 0.781, rf2(0.ext) = 0.77, k = 0.962, k' = 1.019, and RMSEP = 0.460; for 48 bitter-tasting dipeptides, three principal components resulted, with the statistics as: r(2) = 0.950, q(2) = 0.893, RMSEE = 0.152, RMSCV = 0.222, q2(ext)= 0.875, r2(ext) = 0.919, r2(0.ext)= 0.919, rf2(0.ext)= 0.919, k = 1.018, k' = 0.974, and RMSEP = 0.198. In addition, the relationship of ACE-inhibiting activities with bitter-tasting thresholds has been investigated by applying the above-constructed models to predictions on 400 theoretically possible dipeptides. Through analysis, the ACE-inhibiting activities are found to be prominently related to bitter-tasting intensities. Thus, it is deemed to be difficult to find such dipeptides that simultaneously satisfy pharmacodynamic action (high ACE-inhibiting activities) and comfortable tastes, suggesting that active components of dipeptides that are served as functional food to lower blood pressure are not very ideal.