In silico identification of potential inhibitors with higher potency than bumetanide targeting NKCC1: An important ion co-transporter to treat neurological disorders

Abstract

Na + -K + -2Cl-cotransporter 1 (NKCC1) plays an important role in intracellular ionic homeostasis and cell volume regulation in the brain. Pathological activation of brain NKCC1 is associated with many brain disorders, including ischemic stroke, traumatic brain injury, epilepsy, neonatal seizure and autism, suggesting NKCC1 as a potential drug target. Several preclinical and clinical studies used Bumetanide, one of the “loop” diuretic drugs, to inhibit brain NKCC1 activity in neurodevelopmental and neurological disorders. However, poor brain penetration and potent diuretic effect limit its use. Thereby, we selected 1930 compounds, each having the capacity to penetrate into the brain to unmask the best candidates that can act as potent inhibitors for NKCC1 to curb this problem. Molecular docking was performed using PyRx to determine the maximum binding affinities (ranging from −9.3 to 9.0 kcal/mol)among the compounds and the NKCC1 to finally lay out the four top ranked compounds. ADMET analysis revealed that all the four compounds are safer drug candidates and that none of them posed either AMES toxicity or carcinogenicity when filtered on toxicological properties. Selected top-ranked each four compounds along with control (Bumetanide) underwent molecular dynamics (MD) simulations for 100ns each to validate the docking interactions where all four compounds with pubchem CID: (71753382), Pubchem CID:(5740383), Pubchem CID: (71692222) and Pubchem CID: (3442850) are highly supported by root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), radius of gyration (Rg), SASA (Solvent accessible Surface Area) value and Hydrogen bond analysis. Thus, our in silico investigation exhibits all four compounds as potent inhibitors for NKCC1.