Identification of effective and specific serotonin 1B receptor ligands by structure-based virtual screening and molecular dynamics

The serotonergic systems are the most important therapeutic targets for neurological disorders. Many serotonergic drugs have been used to treat neurological disorders, which are well known for their adverse side effects because of the off-target interactions. Development of selective ligands for a specific target is the suitable approach to minimize the off-target interactions and side effects. To identify selective ligands for serotonin 1B receptor (5-HT 1B R), the structural analogs of inverse agonist methiothepin (MT) and natural products were screened against 5-HT 1B R and other 5-HTR subtypes (5-HT 2A R, 5-HT 2B R, and 5-HT 2C R). In the present study, five compounds were selected out of 9963 screened compounds having higher binding affinity with 5-HT 1B R over other 5-HTRs. Amongst them, ZINC31166967 and ZINC31162553 exhibited relatively higher binding affinity towards 5-HT 1B R with the binding energy of − 10.1 and − 9.1 kcal/mol, respectively. The pharmacokinetic assessments considered them safe and non-toxic. Molecular dynamics (MD) simulation revealed the stability of these compounds within the active site of the receptor. The overall analysis suggested that ZINC31166967 and ZINC31162553 may be considered as the selective ligands for 5-HT 1B R. However, detailed experimental investigations will be required to substantiate the findings.