{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T02:44:01Z","timestamp":1783046641583,"version":"3.54.6"},"reference-count":109,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T00:00:00Z","timestamp":1776816000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    Squamous cell carcinoma (SCC) represents a significant oncological challenge. While immune checkpoint inhibitors targeting PD-1\/PD-L1 have revolutionized the treatment of SCC, current monoclonal antibody approaches face limitations, including poor tissue penetration, high costs, and immune-related adverse events in patients. Most existing small-molecule efforts target PD-L1, leaving PD-1\/PD-L2 interactions intact and enabling immune escape. This study represents the first systematic identification of natural product-derived direct PD-1 inhibitors, offering broader pathway blockade compared to PD-L1-selective approaches. While current therapeutic limitations highlight the need for alternative methods, this computational study lays a foundation for experimental validation and potential advancement of a drug development pipeline. Through integrated computational screening of 17,967 phytochemicals from the IMPPAT database, we employed consensus molecular docking across seven algorithms, 300-ns molecular dynamics simulations, density functional theory calculations, and comprehensive ADME profiling. IMPHY004834 (Mahuannin D) from\n                    <jats:italic>Ephedra sinica<\/jats:italic>\n                    emerged as a lead compound with exceptional free binding energy, forming stable interactions with key PD-1. Molecular dynamics analysis revealed remarkable stability with consistent RMSD, lowest RMSF, and sustained hydrogen bonding throughout the simulation. The biflavonoid structure exhibits a favorable HOMO-LUMO gap, indicating chemical stability, while ADME profiling confirms drug-like properties, albeit requiring parenteral administration due to low GI absorption. This work establishes the first evidence for Mahuannin D\u2019s PD-1 inhibitory mechanism, which was previously known only for its cytotoxic effects. It provides a validated computational framework for discovering natural product-based immune checkpoint inhibitors with superior pathway coverage compared to existing PD-L1-selective therapeutics.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0339355","type":"journal-article","created":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T17:29:34Z","timestamp":1776878974000},"page":"e0339355","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["In search of novel PD1 inhibitor from natural products by high-throughput virtual screening and molecular dynamics 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