DDDR-86. AI-driven drug discovery unveils a new compound for superior neuro-anesthesia outcomes via voltage-gated Na channel blockade

Abstract Anesthetics are used across a wide range of inpatient and outpatient procedures and can be administered locally to numb a specific area, regionally to block sensation to larger parts of the body, or generally to induce unconsciousness and full-body analgesia. Although modern anesthetics provide substantial clinical benefits, their use is associated with significant side effects, including postoperative cognitive dysfunction, prolonged numbness, respiratory depression, hypotension, hallucinations, and cardiovascular instability. These adverse effects highlight the ongoing need for novel compounds that maintain or enhance anesthetic efficacy while minimizing the side effect burden. Novel compounds were generated first by starting with the basic structure of lidocaine, then AI-sensing was used to computationally predict beneficial additions or removal of side chains. With the change in subgroups and side chains implemented, the compound was further computationally analyzed in order to ascertain differences observed from the original compounds. Variables for analysis included lipophilicity, half-life, and degree of receptor binding. The generated compound possess an acetamide backbone and an N-methyl substitution, suggesting that it may similarly act as a voltage-gated sodium (Na⁺) channel blocker. However, notable differences exist from lidocaine. The new compound contains methoxy groups rather than methyl groups. This substitution may enhance lipophilicity and CNS penetration through increased electron delocalization via the oxygen atoms. Furthermore, the presence of a pyridyl group in Compound 1 could influence sodium channel subtype selectivity, potentially enhancing its efficacy in treating neuropathic pain. The pyridyl moiety may also alter metabolic pathways by increasing susceptibility to oxidation or conjugation, potentially prolonging the drug’s duration of action. Additionally, the pyridyl group could facilitate binding to other CNS receptors, such as ACh, NMDA, or GABA receptors, possibly resulting in beneficial off-target effects, including anticonvulsant or sedative activity. Compound 1 is theorized to have a pKa of 4.5-5.0 while lidocaine has a pKa of 7.9, meaning that compound 1 is less protonated at the physiological pH of approximately 7.4.