Intriguing the significance of hydrophobic groove by the inhibitory mechanism of mineralocorticoid receptor bound with spironolactone through mutations using long-range molecular dynamics simulations in conjunction with statistical analysis.

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Mineralocorticoid receptor (MR) inhibition using spironolactone, highlighting the importance of crucial residues (N770, Q776 and R817) in the binding site, has been well studied. However, reports on the importance of the hydrophobic groove lined with hydrophobic residues is still lacking. Here, we report the importance of the hydrophobic groove of the MR occupying the thioacetyl moiety of spironolactone. The MR-spironolactone complex was subjected to mutations in the hydrophobic groove by categorizing into three forms viz., 1) the complex completely in its native form, 2) reducing hydrophobicity of the complex and 3) replacing its hydrophobicity and simulated for 1 μs. Our analysis revealed that the residues M807, F829, M845, C849 and M852 at the hydrophobic groove of MR are important in anchoring the thioacetyl moiety of spironolactone along with the residue N770 by providing the conformational stability to spironolactone. Binding free energy calculations of the hydrophobic groove with the binding site included and with the groove separately show the impact of the hydrophobicity of the groove along with the polar residues N770, Q776 and R817. The simulation studies supported with statistical analysis gave clear insights on the hydrophobic groove. The mechanism addressing the role of selected hydrophobic residues F829, M845 and C849 at the hydrophobic pocket through site-directed mutagenesis will shed light on designing novel leads or biomarkers with improved efficiency and potency.

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