The binding of palonosetron and other antiemetic drugs to the serotonin 5-HT3 receptor

Abstract

Inaccurately perceived as niche drugs, antiemetics are key elements of cancer treatment alleviating the most dreaded side effect of chemotherapy. Serotonin 5-HT3 receptor antagonists are the most commonly prescribed class of drugs to control chemotherapy-induced nausea and vomiting (CINV). These antagonists have been clinically successful drugs since the 1980s, yet our understanding of how they operate at the molecular level has been hampered by the difficulty of obtaining structures of drug-receptor complexes. Here, we report the cryo-EM structure of the palonosetron-bound 5-HT3 receptor. We investigate the binding of palonosetron, granisetron, dolasetron, ondansetron, and cilansetron using molecular dynamics, covering the whole set of antagonists used in the clinical practice. The structural and computational results yield detailed atomic insight into the binding modes of the drugs. In light of our data, we establish a comprehensive framework underlying the inhibition mechanism by the -setron drug family.

Structural Determinants for Activity of the Antidepressant Vortioxetine at Human and Rodent 5-HT3receptors

“…Diverse chemical structures thus fit in with only little accommodation of the binding site moiety located on the complementary subunit. The largest differences between structures harboring different ligands lies in deviations of loop C, and more importantly in subunit-subunit interface reorganization (Polovinkin et al, 2018;Zarkadas et al, 2020). In other words, the quaternary structure re-arrangement dominates over tertiary structure deviations.…”

“…For 5-HT3 receptors, structural studies initiated by a crystal structure of a closed state (Hassaïne et al, 2014) now cover a range of conformations assigned to inhibited/resting, pre-active and open states (Basak et al, 2018;Polovinkin et al, 2018;Zhang et al, 2021). Structures are also available for complexes with antiemetic drugs of the -setron class, the major class of clinical drugs targeting the 5-HT3 receptor, which act as competitive antagonists to alleviate the adverse effects of chemotherapies (Basak et al, 2019;Zarkadas et al, 2020). Together, those structures revealed the precise geometry of the ECD and the TMD and how agonist versus antagonist-bound structures differ through reorganizing the ECD quaternary structure.…”

Allostery: The Good, the Bad, and the Ugly

“…This effect is seen with the 5-HT 3 antagonist for chemotherapy therapy-induced nausea palonosetron (Saito and Tsukuda, 2010). Although structural studies suggest palonosetron binds to or near the orthosteric site (Zarkadas et al, 2020) , functional kinetic studies indicate palonosetron is an allosteric modulator having cooperative effects with 5-HT (Rojas et al, 2008). The increased affinity of palonosetron in the presence of 5-HT increases the t 1/2 for dissociation from the receptor by a factor of nearly 10 (t 1/2 for no 5-HT present = 2.3 h: 5-HT present t 1/2 = 21,9 h) (Lummis and Thompson, 2013).…”

Farmacoterapia atual das náuseas e vômitos induzidos por antineoplásicos

“…Nos de primeira geração estão inclusos a odansetrona, dolasetrona e granisetrona. A palonosetrona é um antagonista de segunda geração que possui uma meia-vida mais longa e afinidade maior pelos receptores de serotonina, o que pode explicar uma maior duração nos seus efeitos, e consequentemente maior eficácia em NVIQ na fase retardada (Navari, 2015;Rojas & Slusher, 2015;Zarkadas et al, 2020).…”

“…Os representantes dos antagonistas do receptor de 5-HT3 se encontram na Tabela 1, na qual pode ser observado as principais RAM e o tempo de meia-vida. Rojas & Slusher (2015); Zarkadas et al (2020).…”