Identification of novel peripherally restricted risperidone-like dopamine D2 receptor antagonists for...

Prolactin, a hormone with emerging neuroprotective roles, has demonstrated potential in mitigating cognitive impairment under specific neurotoxic conditions, including environmental toxicity and excitotoxicity. While dopamine D2 receptor (D2R) antagonists, such as risperidone, can elevate systemic prolactin levels to exert beneficial effects in the central nervous system (CNS), their clinical repurposing is constrained by CNS-mediated side effects associated with blood-brain barrier (BBB) penetration. In this study, we aimed to identify novel D2R antagonist candidates predicted to have restricted BBB penetration and the potential to stimulate prolactin secretion without substantial CNS exposure, thereby reducing central side effects including extrapyramidal symptoms and sedation. A systematic multi-stage in silico screening workflow was implemented. Ligand-based virtual screening using SwissSimilarity against the ZINC-20 database identified 400 structural analogs of risperidone. SwissADME-based ADMET filtering selected 226 candidates predicted to be BBB-impermeable, from which molecular docking using AutoDock Vina identified eight compounds with docking scores more favorable than that of risperidone. Subsequent interaction analysis identified four candidates that maintained critical contacts with Asp80 (3.32) and Trp373 (6.48), key residues involved in D2R ligand binding. Molecular dynamics simulations over 100 ns were used to assess conformational behavior, with Compound #128 exhibiting the most favorable ligand stability profile among the tested candidates and showing behavior broadly comparable to that of risperidone. These findings suggest that the identified compounds may serve as computationally prioritized candidates for the development of peripherally restricted D2R antagonists. However, their functional D2R antagonism, actual BBB exclusion, prolactin-elevating activity, and ability to reproduce CNS neuroprotection without direct central D2R modulation remain to be experimentally validated.