Estimand Divergence Between Static Docking and Molecular Dynamics as a Triage Filter for Antimalarial Leads

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.

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BibTeX RIS

BibTeX

@misc{temgoua2026estimand,
  title = {{Estimand Divergence Between Static Docking and Molecular Dynamics as a Triage Filter for Antimalarial Leads}},
  author = {Myke Vital SAO TEMGOUA and Jean-Pierre TCHAPET NJAFA and Penabei SAMAFOU and Fon Wilfred MBACHAM and Serge Guy NANA ENGO},
  howpublished = {ChemRxiv},
  year = {2026},
  month = sep,
  doi = {10.26434/chemrxiv.15009345/v1},
  url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009345/v1},
  note = {CC BY},
}

RIS

TY  - UNPB
TI  - Estimand Divergence Between Static Docking and Molecular Dynamics as a Triage Filter for Antimalarial Leads
AU  - Myke Vital SAO TEMGOUA
AU  - Jean-Pierre TCHAPET NJAFA
AU  - Penabei SAMAFOU
AU  - Fon Wilfred MBACHAM
AU  - Serge Guy NANA ENGO
PY  - 2026
DA  - 2026/09/23
PB  - ChemRxiv
DO  - 10.26434/chemrxiv.15009345/v1
UR  - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009345/v1
AB  - 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.
ER  -

Abstract

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