Codex with GPT-6 Astra demos designing antimalarial small molecules
Using LDDM to generate candidate molecules and running retrosynthesis and docking scoring, the candidates bound comparably to DSM265, though no complete synthesis route was found.
“Codex, please design some small molecules to fight malaria.” In this tool calling demo, Codex with GPT-6 Astra used LDDM to generate candidate molecules which might bind Plasmodium falciparum's dihydroorotate dehydrogenase, an enzyme the malaria parasite needs to make pyrimidines. Disrupting this enzyme can stop the parasite from replicating. Codex used LDDM in two ways: 1) de novo molecule generation 2) extending a fixed fragment of the existing dehydrogenase inhibitor, DSM265 DSM265 was reported by Coteron et al in 2011. This demo uses its experimentally determined binding pocket in PDB 4RX0. The attached vid shows the LDDM generation steps. The LDDM generated candidates had no exact matches in Astra's PubChem and ChEMBL searches, and the de novo molecule had no >85% similar hits. Codex used retrosynthesis tools (AiZynthFinder, Syntheseus, and SynPlanner) to search for routes to make these, but no complete routes were found during the demo. Codex used RDKit and PoseBusters to check geometry and protein/cofactor clashes (no severe clashes). Codex also used AutoDock Vina to score fit in the pocket and these computational candidates scored similarly to DSM265.
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