Insights from molecular dynamics simulations to exploit new trends for the development of improved opioid drugs

Abstract

Having accidental deaths from opioid overdoses almost quadrupled over the past fifteen years, there is a strong need to develop new, non-addictive medications for chronic pain to stop one of the deadliest epidemics in American history. Given their potentially fewer on-target overdosing risks and other adverse effects compared to classical opioid drugs, attention has recently shifted to opioid allosteric modulators and G protein-biased opioid agonists as likely drug candidates to prevent and/or reverse opioid overdoses. Understanding how these molecules bind and activate their receptors at an atomistic level is key to developing them into effective new therapeutics, and molecular dynamics-based strategies are contributing tremendously to this understanding.

Biased, Bitopic, Opioid–Adrenergic Tethered Compounds May Improve Specificity, Lower Dosage and Enhance Agonist or Antagonist Function with Reduced Risk of Tolerance and Addiction

“…One of the explicit assumptions of this review is therefore that allosteric binding sites for adrenergic compounds exist on the extracellular side of the orthosteric opioid binding site (Figures 1-3) as imputed from the binding studies and enhancement documented above. Notably, Traynor's group [104-107], Filizola's group [108][109][110], and Matosiuk's group [111,112] have each studied small molecule, non-adrenergic allosteric enhancers of opioid receptors and, using molecular dynamics studies, also located allosteric binding to a site extracellular to the orthosteric site and often involving transmembrane-to-extracellular loop regions as illustrated in Figures 1-3. Additionally, Uprety et al [113] demonstrated the existence of a computationally, synthetically, and pharmacologically validated allosteric binding site in MOR and KOR that involves the same transmembrane 5-extracellular loop 2 region identified in adrenergic binding studies (above).…”

Comprehensive overview of biased pharmacology at the opioid receptors: biased ligands and bias factors

“…TRV250 178 , which currently finished phase I clinical trials, is a G protein-biased DOR agonist that preferentially activates the G protein pathway showing reduced hyperalgesia in rodent models. In these studies, TRV250 is developed for the treatment of acute migraine and was shown to have a quick absorption of 0.5 to 2 hours upon s.c. administration, which increased by up to 3 hours upon oral administration and by up to 6 hours in conjunction with a high-fat meal.…”

Molecular Basis of Opioid Action: From Structures to New Leads

“…Optimization of allosteric modulators, however, remains challenging, in part due to a lack of experimental high-resolution structures of opioid receptors bound to such molecules. Classic pharmacological studies and molecular dynamics simulations have begun to fill this gap (34)(35)(36). Further characterization of allosteric sites will likely enable not only ways to potentiate opioidergic signaling, but also potential avenues for opioid antagonists effective in reversing the effect of exceptionally potent opioids such as carfentanil (37).…”