Abstract

DESIGN AND IN-SILICO EVALUATION OF NOVEL ZURANOLONE DERIVATIVES FOR THE TREATMENT OF POSTPARTUM DEPRESSION

P. Chithra*, Khadeejath Amana C. K., Lubna Harif, Mariyam Bashreena

Abstract

Postpartum depression (PPD) is a serious mood disorder that affects millions of women worldwide, often emerging in the months following childbirth. Unlike the transient ―baby blues,‖ PPD can persist and disrupt maternal well-being, infant bonding, and family dynamics. Current treatments, such as SSRIs and SNRIs, act slowly and do not directly address the neurosteroid imbalance thought to underlie PPD. Zuranolone, a synthetic neurosteroid that enhances GABA-A receptor activity, has shown faster symptom relief, but its pharmacokinetic limitations highlight the need for improved derivatives. In this study, novel Zuranolone derivatives were designed using bioisosteric replacement of the pyrazole ring with imidazole, thiadiazole, and oxadiazole heterocycles. Their physicochemical properties were predicted using SwissADME, and blood–brain barrier permeability was assessed with logBBpred. Molecular docking against the native GABA-A receptor (PDB ID: 8FOI) revealed stronger receptor interactions than allopregnanolone, with the imidazole derivative (ZI1) showing the most favourable profile, including optimal lipophilicity, high gastrointestinal absorption, and superior docking affinity. These findings suggest that structural modification of Zuranolone may enhance its therapeutic potential in PPD. However, as the results are based solely on computational predictions, laboratory synthesis and experimental validation are essential to confirm feasibility, activity, safety, and clinical relevance.

Keywords: Postpartum depression, Zuranolone, GABA receptor, allopregnanolone, imidazole.