Do topological and quantum-inspired molecularrepresentations add value? Evidence from Africannatural-product-inspired antimalarial chemical space
4 affiliations
- 1Department of Physics, Faculty of Science, University of Yaoundé, P.O. Box 812, Yaoundé, Cameroon
- 2Department of Medical Imaging and Radiation Sciences
- 3Université de Sherbrooke
- 4Faculty of Science, University of Yaoundé, P.O. Box 812, Yaoundé, Cameroon
Abstract
Topological and quantum-inspired molecular representations are increasingly proposed for drug discovery, but their predictive value relative to classical fingerprints on naturalproduct chemical space remains unclear.We benchmark a persistent-homology Topological Fingerprint (TFP), a Tucker-compressed Tensor Network Embedding (TNE), and simulated Quantum Kernel Scores (QKS) against classical baselines on 19 849 computationally generated candidates inspired by African natural-product antimalarials, with computationally predicted activity labels.Persistent homology decomposes the scaffold paradox into conserved H 1 ring features and divergent H 0 connectivity: 92.6 % of expanded molecules are whole-molecule Tanimoto-distinct from seeds while 69.3 % retain seed scaffolds.TNE compresses molecular tensors to 192 elements at 6.1× real-atom compression (reconstruction error 0.113) and retains docking-score-predictive information, competitively on PfDHFR (R 2 = 0.473 versus 0.461 for ECFP4) though below ECFP4 on PfATP4 and PfCRT.For activity prediction (n = 19 836, 5-fold cross-validation), ECFP4 achieves AUC 0.948 under random splitting and 0.822 when folds are grouped by Bemis-Murcko scaffold, the panel spanning only 632 scaffolds; the hybrid (TFP+TNE+QK) reaches 0.888, with QKS the principal contributor within that hybrid (∆ = -0.040),which nonetheless remains below ECFP4.Stacking TFP and TNE onto ECFP4 changed AUC by -0.000 2 (p = 0.084).The quantum kernel was not detectably different from a tuned RBF internally (p = 0.060) and performed lower on the ChEMBL label-source-shift panel (AUC 0.817 versus 0.847; p = 0.021).These representations add diagnostic and interpretive information under the tested protocols, but not predictive performance beyond ECFP4.
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BibTeX
@misc{temgoua2026topological,
title = {{Do topological and quantum-inspired molecularrepresentations add value? Evidence from Africannatural-product-inspired antimalarial chemical space}},
author = {Myke Vital Sao Temgoua and Jean-Pierre TCHAPET NJAFA and Serge Guy Nana Engo and Penabei Samafou and Wilfred Fon Mbacham},
howpublished = {ChemRxiv},
year = {2026},
month = sep,
doi = {10.26434/chemrxiv.15007167/v2},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15007167/v2},
note = {CC BY},
}
RIS
TY - UNPB
TI - Do topological and quantum-inspired molecularrepresentations add value? Evidence from Africannatural-product-inspired antimalarial chemical space
AU - Myke Vital Sao Temgoua
AU - Jean-Pierre TCHAPET NJAFA
AU - Serge Guy Nana Engo
AU - Penabei Samafou
AU - Wilfred Fon Mbacham
PY - 2026
DA - 2026/09/20
PB - ChemRxiv
DO - 10.26434/chemrxiv.15007167/v2
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15007167/v2
AB - Topological and quantum-inspired molecular representations are increasingly proposed for drug discovery, but their predictive value relative to classical fingerprints on naturalproduct chemical space remains unclear.We benchmark a persistent-homology Topological Fingerprint (TFP), a Tucker-compressed Tensor Network Embedding (TNE), and simulated Quantum Kernel Scores (QKS) against classical baselines on 19 849 computationally generated candidates inspired by African natural-product antimalarials, with computationally predicted activity labels.Persistent homology decomposes the scaffold paradox into conserved H 1 ring features and divergent H 0 connectivity: 92.6 % of expanded molecules are whole-molecule Tanimoto-distinct from seeds while 69.3 % retain seed scaffolds.TNE compresses molecular tensors to 192 elements at 6.1× real-atom compression (reconstruction error 0.113) and retains docking-score-predictive information, competitively on PfDHFR (R 2 = 0.473 versus 0.461 for ECFP4) though below ECFP4 on PfATP4 and PfCRT.For activity prediction (n = 19 836, 5-fold cross-validation), ECFP4 achieves AUC 0.948 under random splitting and 0.822 when folds are grouped by Bemis-Murcko scaffold, the panel spanning only 632 scaffolds; the hybrid (TFP+TNE+QK) reaches 0.888, with QKS the principal contributor within that hybrid (∆ = -0.040),which nonetheless remains below ECFP4.Stacking TFP and TNE onto ECFP4 changed AUC by -0.000 2 (p = 0.084).The quantum kernel was not detectably different from a tuned RBF internally (p = 0.060) and performed lower on the ChEMBL label-source-shift panel (AUC 0.817 versus 0.847; p = 0.021).These representations add diagnostic and interpretive information under the tested protocols, but not predictive performance beyond ECFP4.
ER -