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- W2289952387 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)." @default.
- W2289952387 created "2016-06-24" @default.
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- W2289952387 date "2015-07-29" @default.
- W2289952387 modified "2023-10-16" @default.
- W2289952387 title "Higher-Affinity Agonists of 5-HT<sub>1A</sub>R Discovered through Tuning the Binding-Site Flexibility" @default.
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- W2289952387 doi "https://doi.org/10.1021/acs.jcim.5b00164" @default.
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