Targeting programmed cell death 4 (PDCD4) with biogenic compounds in ARDS by Gaussian process‐based QSAR virtual screening

The programmed cell death 4 (PDCD4) has recently been recognized as a new and attractive target of acute respiratory distress syndrome. Here, we attempted to discover new and potent PDCD4 mediator ligands from biogenic compounds using a synthetic strategy of statistical virtual screening and experimental affinity assay. In the procedure, a Gaussian process‐based quantitative structure‐activity relationship regression predictor was developed and validated statistically based on a curated panel of structure‐based protein‐ligand affinity data. The predictor was integrated with pharmacokinetics analysis, chemical redundancy reduction, and flexible molecular docking to perform high‐throughput virtual screening against a distinct library of chemically diverse, drug‐like biogenic compounds. Consequently, 6 hits with top scores were selected, and their binding affinities to the recumbent protein of human PDCD4 were identified, 3 out of which were determined to have high or moderate affinity with K_d at micromolar level. Structural analysis of protein‐ligand complexes revealed that hydrophobic interactions and van der Waals contacts are the primary chemical forces to stabilize the complex architecture of PDCD4 with these mediator ligands, while few hydrogen bonds, salt bridges, and/or π‐π stacking at the complex interfaces confer selectivity and specificity for the protein‐ligand recognition. It is suggested that the statistical Gaussian process‐based quantitative structure‐activity relationship screening strategy can be successfully applied to rational discovery of biologically active compounds. The newly identified molecular entities targeting PDCD4 are considered as promising lead scaffolds to develop novel chemical therapeutics for acute respiratory distress syndrome.