Molecular Mechanisms and Optimization Strategies for the Impact of Antihypertensive, Lipid-Lowering, and Antidiabetic Drugs on Gut Microbiota

Patients often suffer from hypertension, hyperlipidemia, and diabetes, requiring long-term polypharmacy. These drugs may alter gut microbiota composition, leading to adverse effects, but the underlying mechanisms are unclear. We selected 23 common drugs from ChEMBL, identified their metabolites via DrugBank, and used TargetNet and GeneCardsSuite to find drug targets and human proteins. Cross-analysis revealed 15 shared human side-effect protein targets. Molecular docking and Structure–activity relationship analyses assessed interactions with human and bacterial proteins. Eight compounds, including metabolites of amlodipine, metoprolol, glipizide, and fenofibrate, showed significant binding to human and gut bacterial proteins. Based on our in silico models, we predict that specific structural modifications could potentially enhance efficacy while minimizing microbial disruption and adverse reactions. Molecular dynamics simulations suggest that these modified drugs might computationally maintain therapeutic interactions while reducing gut microbiota disruption. Our findings highlight the impact of these drugs on gut microbiota and side effects via shared protein targets. Supported by in silico models and preliminary in vitro assays, we think that precision medicine, probiotic co-administration, or drug structure modifications could potentially serve as future strategies to mitigate complications and side effects in elderly patients, warranting further in vivo and clinical validation.