title: Higher-Affinity Agonists of 5-HT1AR Discovered through Tuning the Binding-Site Flexibility.
abstract: Discovery of high-affinity and high-selectivity agonists of 5-HT1AR has become very attractive due to their potential therapeutic effects on multiple 5-HT1AR-related psychological and neurological problems. On the basis of our previously designed lead compound FW01 (Ki = 51.9 nM, denoted as 9a in the present study), we performed large-scale molecular dynamics simulations and molecular docking operations on 5-HT1AR-9a binding. We found the flip-packing events for the headgroup of 9a, and we also found that its tail group could bind flexibly at the agonist-binding site of 5-HT1AR. By finely tuning the flip-packing phenomenon of the 9a headgroup and tuning the binding flexibility of 9a tail group, we virtually designed a series of new 9a derivatives through molecular docking operations and first-principles calculations and predicted that these newly designed 9a derivatives should be higher-affinity agonists of 5-HT1AR. The computational predictions on the new 9a derivatives have been confirmed by our wet-experimental studies as chemical synthesis, binding affinity assays, and agonistic-function assays. The consistency between our computational design and wet-experimental measurements has led to our discovery of higher-affinity agonists of 5-HT1AR, with ∼50-fold increase in receptor-binding affinity and ∼25-fold improvements in agonistic function. In addition, our newly designed 5-HT1AR agonists showed very high selectivity of 5-HT1AR over subtype 5-HT2AR and also over three subtypes of dopamine receptors (D1, D2, and D3).
authors.affiliation: Department of Medicinal Chemistry & Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University , Shanghai 201203, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Lian
authors.affiliation: Jiangsu Key Laboratory for Translational Research for Neuropsychiatric-Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University , Suzhou 215123, China.
authors.forename: LinLang
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Medicinal Chemistry & Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University , Shanghai 201203, China.
authors.forename: Chuanrong
authors.initials: C
authors.lastname: Geng
authors.affiliation: Jiangsu Key Laboratory for Translational Research for Neuropsychiatric-Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University , Suzhou 215123, China.
authors.forename: Xuechu
authors.initials: X
authors.lastname: Zhen
authors.affiliation: Department of Medicinal Chemistry & Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University , Shanghai 201203, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Fu
mesh_terms: D001665:Binding Sites; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D044282:Receptor, Serotonin, 5-HT1A / Q000737:chemistry / Q000378:metabolism*; D044402:Receptor, Serotonin, 5-HT2A / Q000737:chemistry / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D058825:Serotonin 5-HT1 Receptor Agonists / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D044402:Receptor, Serotonin, 5-HT2A; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D058825:Serotonin 5-HT1 Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A