Kinetic Compatibility as a Predictor of PTP1B Inhibitor Combination Outcomes: An Integrated Experimental and Computational Study
Abstract
Although chlorogenic acid, suramin, ursolic acid, and the glycyrrhetinic acid derivative FC122 are individually known PTP1B inhibitors, no study has systematically characterized how mechanistic diversity determines the pharmacological outcome of their combinations. Here, we integrate experimental enzyme kinetics, molecular docking, molecular dynamics (MD), and membrane permeability simulations to address this question. Individual inhibitory potencies ranked SUR > FC122 > UA > CGA (IC50: 1.82, 3.27, 6.12, and 252 µM, respectively). Fixed-ratio combination experiments showed two distinct profiles: additivity for the uncompetitive + mixed pair (FC122 + UA) and competitive + competitive pairs (SUR + CGA), and antagonism for the competitive + uncompetitive combination (SUR + FC122). Docking and MD provided the structural basis for these results and suggested that each combination imposes a distinct structural flexibility profile on the disordered C-terminal region of PTP1B (residues 300-400). For the first time, the MD-AMBER-Umbrella-COM protocol was applied to generate a comparative membrane permeability profile for mechanistically diverse PTP1B inhibitors, proposing a permeability order (SUR > FC122 > CGA ≈ UA). These results suggest that kinetic compatibility is a more reliable predictor of promising inhibitor combinations than binding-site geography alone, and they offer a rational framework for designing multisite PTP1B inhibition strategies in type 2 diabetes mellitus.
Read the paper
Related studies
- Metformin as an adjuvant in breast cancer treatment
- Metformin Lysosomal Targeting: A Novel Aspect to Be Investigated for Metformin Repurposing in Neurodegenerative Diseases?
- Aberrant HSF1 signaling activation underlies metformin amelioration of myocardial infarction in mice
- Metformin induces ZFP36 by mTORC1 inhibition in cervical cancer-derived cell lines
- Protein Interaction Network for Identifying Vascular Response of Metformin (Oral Antidiabetic)
- Preventing Long COVID With Metformin
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.