Anti-target chemical-space coverage of Indian medicinal plant phytochemicals

Computational safety evaluation of phytochemical libraries commonly relies on models trained on experimentally tested compounds and applied to much larger and chemically diverse collections. An important but often overlooked question is whether predicted compounds are adequately represented within the experimental chemical space underlying these models. Here, we examined this question for the Indian Medicinal Plants, Phytochemistry and Therapeutics (IMPPAT) database using experimentally characterized datasets for three anti-target endpoints: hERG blockade, cytochrome P450 (CYP) inhibition, and pregnane X receptor (PXR) induction. After structure standardization, 14,956 unique IMPPAT compounds were compared with 8,877 hERG, 4,905 CYP, and 4,138 PXR reference compounds using consensus nearest-neighbor similarity based on Morgan and atom-pair fingerprints. At a Tanimoto similarity threshold of 0.80, only 0.92%, 0.30%, and 0.46% of IMPPAT compounds had close measured analogs in the hERG, CYP, and PXR datasets, respectively. Relative to the internal nearest-neighbor distributions of the reference datasets, a typical IMPPAT compound lay near the 1st percentile, indicating substantial chemical-space separation. Compounds with close experimental analogs also showed distinct molecular characteristics, with descriptor-based logistic regression yielding cross-validated AUC values of 0.77-0.80. Plant-level enrichment was markedly reduced after excluding widely distributed metabolites and was further restricted when the nearest measured analog was required to have pIC50 or pEC50 ≥ 5. The remaining signals were concentrated in a limited number of taxa, including Rauvolfia, Sinopodophyllum/Dysosma, Cinchona, and Catharanthus roseus. Overall, most IMPPAT phytochemicals lack close structural representation among currently measured anti-target compounds. Computational safety predictions for these molecules should therefore be interpreted as extrapolations and accompanied by explicit measures of structural support. Absence of a close experimental analog should be regarded as a gap in available evidence rather than evidence of safety.