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

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.