Estimand Divergence Between Static Docking and Molecular Dynamics as a Triage Filter for Antimalarial Leads
Year: 2026
Type: preprint
Abstract: Using a curated collection derived from 396 African natural products and 454 synthetic antimalarials, we evaluated a multi-target docking framework across 136 wild-type and mutant receptor states of PfDHFR and PfCRT.On a primary candidate cohort (n = 12), a Resistance-Resilience Score (RRS) provided a five-tier stratification decoupling predicted wild-type binding strength from mutant-state score retention.Explicit-solvent molecular dynamics (MD) simulations showed a directional divergence in 87.5 % (7/8; 95% Wilson CI 52.9-97.8%, n = 8) of matched candidate-target states, wherein dynamic pocket relaxation retained poses where static grid docking predicted score penalties.At single-replicate scope this divergence is a protocol-local calibration signal: static docking scores and short MD trajectories provide complementary, non-equivalent triage metrics for natural product lead optimization.
Source: ChemRxiv
Institutions: Université de Yaoundé I, Université de Sherbrooke
Language: English
Subfield: Drug Discovery
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7214114401