An alternative biomimetic tool – Dual hydrophilic/reversed-phase interaction mode

Abstract

During the early stages of drug discovery, it becomes increasingly important to acquire a basic physico-chemical and pharmacokinetic profile of drug candidates using efficient and cost-effective laboratory and computational models. In this study, the possibility of applying the dual hydrophilic interaction liquid chromatography/reversed-phase mode (HILIC/RP) as a alternative biomimetic tool for the preliminary profiling of imidazoline and piperazine-related compounds was investigated. Their retention behaviour on the mixed-mode HILIC/RP column was described as a dependence of the logarithm of the retention factor (logk) in relation to the volume fraction of the water component in the mobile phase (φ). The retention was quantified by integration of HILIC (logkH), RP (logkR) and the total HILIC/RP (logkA) area under the logk = f(φ) curve. The biomimetic capabilities of HILIC/RP mode were observed through physico-chemical and pharmacokinetic interpretation of chromatographic behaviour. The physico-chemical characteristics of the HILIC/RP mode were defined based on linear solvation energy relationships, genetic algorithm-multiple linear regression and Boruta-XGBoost predictive modeling. The created models showed reliable predictive performances for defining the logkA, logkR, and logkH values. The mixed-mode logkA, logkR, and logkH parameters correlate well with physico-chemical (e.g., lipophilicity indices) and basic pharmacokinetic properties of the examined compounds. The models created have confirmed that the simultaneous contribution of both HILIC/RP mechanisms can be used to accurately evaluate the key properties of newly synthesized imidazoline and piperazine-related compounds while reducing costs and selecting suitable candidates in the early stages of drug development and discovery.