Structure-Based Virtual Screening Identifies Ritobegron and Resveratrol as Dual Inhibitors of NMDA and PTP-1B for Alzheimer’s Disease Therapy

Abstract

Many Alzheimer’s disease (AD) drug candidates fail during clinical translation due to poor target validation and inadequate penetration across the blood–brain barrier. This study aimed to identify potential inhibitors for AD by targeting N-methyl-D-aspartate (NMDA) and protein tyrosine phosphatase 1B (PTP1B). A total of 2,399,743 molecules retrieved from the ChEMBL database were filtered using various in silico techniques to identify small, investigational molecules under phase III clinical trial, that are safe, bioavailable with favourable physicochemical properties. The top-ranked molecules were subjected to molecular docking studies on NMDA and PTP1B. A total of 1,920,643 small molecules were identified, among which 1,110 investigational molecules had advanced to phase III clinical trials. Of these, 298 molecules met the Lipinski Rule of Five and were considered safe, and ultimately only 3 molecules demonstrated favourable physicochemical properties. Ritobegron, docked with PTP1B, showed a binding energy, E of -8.69 kcal/mol and an inhibition constant, Ki of 0.424 µM, outperforming the native ligand (-7.23 kcal/mol, 5.04 µM) and with NMDA showed E of -8.06 kcal/mol and Ki of 1.23 µM, both superior to its native ligand (-7.40 kcal/mol, 3.74 µM). Resveratrol, docked with protein PTP1B, showed E of –7.59 kcal/mol and Ki of 2.53 µM, slightly more negative than the native ligand (–7.23 kcal/mol, 5.04 µM). These interactions involved hydrogen bonding, pi-stacking, and hydrophobic interactions with key amino acid residues. The study suggests that ritobegron and resveratrol could serve as promising inhibitors for NMDA receptors and PTP1B enzyme, offering potential therapeutic avenues for AD treatment.