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).

As the largest family of integral membrane proteins, G-protein-coupled receptors (GPCRs) comprise the largest class of therapeutic targets that aimed approximately 40% of modern medicinal drugs. Understanding the agonist/ antagonist mechanism, as well as the signal transduction of the GPCRs, is pivotal in drug discovery and new therapeutic strategy development. In the past few years, determination of high-resolution crystal structures of GPCRs from different subfamilies laid a solid foundation for both experimental and computational studies on GPCR-related diseases. Dopamine and serotonin receptors that belong to class A GPCRs play key roles in psychotic disorders, such as schizophrenia. As a robust approach, computer-aided drug design (CADD) has been demonstrated to be a powerful tool to discover novel drugs against these disorders and to help understand the activation mechanism of related receptors. Herein, we reviewed the recent progresses on CADD-based drug discovery, agonist/antagonist mechanism, and agonist-induced signaling mechanism in dopamine and serotonin receptors.