Computational Drug Repurposing Reveals Lopinavir and Ritonavir as Potential Inhibitors of APOL Proteins for Combating Kidney and Neuropsychiatric Disorders.

INTRODUCTION

The Apolipoprotein L (APOL) family, particularly APOL1, APOL2, and APOL4, has been implicated in the pathogenesis of kidney injury, neuroinflammation, and several psychiatric disorders. However, there are currently no approved drugs available that can directly target these proteins, except for some APOL1-directed therapeutics. Identifying compounds that can modulate multiple APOL paralogs may therefore offer a promising therapeutic approach.

METHODS

In this study, a structure-based drug repurposing approach integrating molecular docking and MD simulations was employed to identify potential inhibitors of three APOL proteins. A library of 1,040 FDA-approved compounds was screened against APOL1, APOL2, and APOL4, followed by MD simulations to evaluate the stability and affinity of the identified complexes.

RESULTS

Docking analysis identified the antiviral drugs lopinavir and ritonavir as top-ranked potential inhibitors across all three APOL proteins. Ritonavir showed the strongest predicted binding affinity toward APOL1 (-10.46 kcal/mol) and APOL2 (-9.66 kcal/mol), while lopinavir exhibited the highest affinity for APOL4 (-9.21 kcal/mol). Subsequent MD simulations combined with RMSD, RMSF, RoG, hydrogen-bond, PCA, DCCM, and FEL analyses provided computational support for the persistence of the predicted protein-ligand interactions. MM/GBSA calculations further supported favorable predicted binding, with total energies ranging from -42.97 to -65.55 kcal/mol.

DISCUSSION: The identification of predicted shared inhibitors for APOL1, APOL2, and APOL4 is biologically significant due to their conserved structural features and overlapping pathological pathways. Repurposing clinically approved antivirals with established clinical use may provide a starting point for further investigation of APOL-targeting strategies.

CONCLUSION

This study provides the first computational evidence supporting cross-paralog APOL inhibition by repurposed antiviral drugs. These findings provide a computational basis for the development of APOL-targeted therapeutic strategies and warrant further experimental validation.