Integrated in silico identification of fungal-derived dual-target inhibitors for anti-schistosomal drug discovery
- 1Primeasia University, Dhaka-1213, Bangladesh
Abstract
Praziquantel, which has limited efficacy against young parasites and reduces susceptibility, is the principal therapy for schistosomiasis, a neglected tropical illness. This work identified fungal-derived compounds with potential dual inhibitory action against Schistosoma mansoni DHODH and cathepsin B1 using an integrated computational method. From 1,831 fungal metabolites, 120 were selected for molecular docking after structure standardisation, drug-likeness evaluation, ADMET, and toxicity screening. Ganoderlactone B (CID_122184973) and Spiroapplanatumine F (CID_132962217) strongly bound to DHODH and CB1, with docking affinities of -10.6 and -10.0 kcal/mol and -9.0 and -8.9, respectively. Docking validation showed good discrimination between active compounds and decoys with area-under-the-curve values of 0.98 for DHODH and 0.96 for CB1. The protein-ligand interaction study showed hydrogen bonding, hydrophobic interactions, and van der Waals contacts at the binding sites. In 100 ns molecular dynamics simulations, protein complexes exhibited modest backbone deviations and maintained compactness, although CID_132962217 showed sustained binding and a constrained conformation. MM-PBSA analysis identified CID_122184973 as the best common ligand for both targets. At the B3LYP/6-31G level, density functional theory calculations showed that CID_139584993 had the lowest HOMO-LUMO energy gap and hardness values of 3.552 and 1.776 eV, respectively, and the highest softness value of 0.282 eV-1, indicating greater electronic reactivity. Electrostatic potential mapping and QSAR predictions supported their interaction and antiparasitic potential. Overall, CID_122184973 and CID_132962217 are promising fungal scaffolds for dual-target anti-schistosomal drug development. Experimental enzyme inhibition, parasite viability, toxicity, and in vivo research are needed to confirm computational findings.
Related
- Identification of new fucosyltransferase-8 inhibitors: An integrated biochemical, biophysical, and computational approach
- Fragment-Based Discovery of KLK6 and KLK7 Inhibitors
- Identification of Cysteine-Reactive Early Mitotic Inhibitors
- Prime editing enables high-throughput identification and characterization of selective MutSβ inhibitors
- Discovery of Stereoselective Targeted Covalent Inhibitors of the RAB27-Effector Protein-Protein Interaction.
BibTeX
@misc{paul2026integrated,
title = {{Integrated in silico identification of fungal-derived dual-target inhibitors for anti-schistosomal drug discovery}},
author = {T. Paul and M. Al-Amin and U. Shill and N. Tabassum and K. Fatema and E. A. Rial and M. K. Sarkar and A. A. Mahdeen and A. Majumder and A. Naher and F. F. Auishe and F. B. Khan and F. Ahmad and H. B. Afridy and M. A. Iqbal and A. Biswas and K. F. Sultana and S. Dutta and S. Bashar},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.04.749322},
url = {https://www.biorxiv.org/content/10.64898/2026.09.04.749322v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Integrated in silico identification of fungal-derived dual-target inhibitors for anti-schistosomal drug discovery
AU - T. Paul
AU - M. Al-Amin
AU - U. Shill
AU - N. Tabassum
AU - K. Fatema
AU - E. A. Rial
AU - M. K. Sarkar
AU - A. A. Mahdeen
AU - A. Majumder
AU - A. Naher
AU - F. F. Auishe
AU - F. B. Khan
AU - F. Ahmad
AU - H. B. Afridy
AU - M. A. Iqbal
AU - A. Biswas
AU - K. F. Sultana
AU - S. Dutta
AU - S. Bashar
PY - 2026
DA - 2026/09/04
PB - bioRxiv
DO - 10.64898/2026.09.04.749322
UR - https://www.biorxiv.org/content/10.64898/2026.09.04.749322v1
AB - Praziquantel, which has limited efficacy against young parasites and reduces susceptibility, is the principal therapy for schistosomiasis, a neglected tropical illness. This work identified fungal-derived compounds with potential dual inhibitory action against Schistosoma mansoni DHODH and cathepsin B1 using an integrated computational method. From 1,831 fungal metabolites, 120 were selected for molecular docking after structure standardisation, drug-likeness evaluation, ADMET, and toxicity screening. Ganoderlactone B (CID_122184973) and Spiroapplanatumine F (CID_132962217) strongly bound to DHODH and CB1, with docking affinities of -10.6 and -10.0 kcal/mol and -9.0 and -8.9, respectively. Docking validation showed good discrimination between active compounds and decoys with area-under-the-curve values of 0.98 for DHODH and 0.96 for CB1. The protein-ligand interaction study showed hydrogen bonding, hydrophobic interactions, and van der Waals contacts at the binding sites. In 100 ns molecular dynamics simulations, protein complexes exhibited modest backbone deviations and maintained compactness, although CID_132962217 showed sustained binding and a constrained conformation. MM-PBSA analysis identified CID_122184973 as the best common ligand for both targets. At the B3LYP/6-31G level, density functional theory calculations showed that CID_139584993 had the lowest HOMO-LUMO energy gap and hardness values of 3.552 and 1.776 eV, respectively, and the highest softness value of 0.282 eV-1, indicating greater electronic reactivity. Electrostatic potential mapping and QSAR predictions supported their interaction and antiparasitic potential. Overall, CID_122184973 and CID_132962217 are promising fungal scaffolds for dual-target anti-schistosomal drug development. Experimental enzyme inhibition, parasite viability, toxicity, and in vivo research are needed to confirm computational findings.
ER -