Fig. 5: Drug docking and prioritization of SARS-CoV-2–human interaction inhibitors.

a, Validation of smina’s ability to identify the correct binding site from the full protein surface based on 4,399 drug–ligand pairs across 95 protein targets. Docking was carried out either by re-docking each ligand back into its native protein structure or cross-docking each ligand into a representative receptor structure. Baseline performance expectation derived from random selection of surface patches matching the size of the correct binding site is shown for comparison. Each line and shaded area indicates the percentage of docks that correctly identify X binding site residues ± s.d. as estimated by 1,000-fold bootstrapping sampling 95 drug–target pairs with replacement each iteration. The gray shaded area (top) indicates the maximum fraction of docks whose true binding sites contain at least X residues. b, Protein–protein and protein–drug binding sites pooled across 16 applicable drug–target pairs were significantly enriched (log₂OR = 1.38, P = 2.1 × 10⁻⁷ by two-sided z-test). Data are presented as log₂OR ± s.e.m. c, Individual breakdown of the overlap between the each of the protein–protein and protein–drug binding sites as either undockable (no protein–protein docked structure available for comparison; 14 total), no overlap (7 total), partial overlap (1 total) or significant overlap (8 total). The individual log₂OR for each of the significant drug target pairs are shown. Data are presented as log₂OR ± s.e.m. The MARK3–ZINC95559591 pair (shown in d) is highlighted in red. d, Docked structure for ZINC95559591 bound to human MARK3. MARK3 surface is colored either green (non-interface, n = 270), blue (orf9b interface, n = 28), red (ZINC95559591 interface, n = 3) or magenta (shared interface, n = 12). Cut-out display highlights the MARK3–ZINC95559591 binding site. Polar contacts between MARK3 and ZINC95559591 are shown as dashed lines. e, Corresponding docked structure for SARS-CoV-2 orf9b bound to human MARK3.