Investigating the interaction of indapamide and its derivatives with phosphorylated human NCC: a multi-scale computational method

Abstract Diuretics used to manage hypertension are often framed around the sodium-chloride cotransporter (NCC) due to Indapamide's renal depleting effects, yet NCC's role in electrolyte balance remains actively untargeted within clinical settings. This study integrated computational NCC modeling concepts like crystal structure prediction and docking simulations, creating molecular dynamics frameworks for the three novel Indapamide ester derivatives (Ind-1, Ind-2, Ind-3), to evaluate phosphorylated NCC docking criteria and establish binding control mechanisms. Ind-1 and Ind-3 demonstrated the strongest docking capabilities, displaying remarkable stability in complex formation with phosphate NCC that relied heavily on expansive hydrogen bonding alongside non-covalent interactions. Electronic structure analysis of HOMO-LUMO gaps alongside increased electronegativity further validated binding strength projections alongside ADME implications, which attributed favorable pharmacokinetics to Ind-1 and Ind-3 despite limited gastrointestinal absorption for Ind-3. These outcomes help NCC diuretic designers optimize therapeutic techniques and maneuver molecular architecture toward more potent but easier to control medications.