Structureless

Heart failure switches off OPLAH—a protective enzyme that clears a toxic metabolite—and no one had mapped where its known activator binds because OPLAH has no solved structure. No binding site, no way to design a better activator. We built a pipeline that finds the site without assuming it. From an AlphaFold model of OPLAH (1,288 aa, no experimental structure), we detected every pocket across the whole protein with two geometry methods (P2Rank, fpocket), then docked 5′-AMP — the activator our team identified earlier in a 1,280-compound screen — completely blind, with no pocket specified. Three independent methods converge on the same site: 17 residues fold around it, with a D-x-G-G-T phosphate motif repeated twice. Then we screened 5,000 compounds against that pocket. The top hit (ZINC4126706) shares almost none of AMP's chemistry yet outranks it, and 379 novel scaffolds beat AMP overall a shortlist to test at the bench, not measured affinities. Why it matters: nothing in the method is specific to OPLAH. Any target with a predicted structure and one known modulator can run the same unbiased search and thousands are stuck exactly where OPLAH was

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