In silico evaluation of novel isosteres against PTPN1 and estrogen receptor alpha: molecular docking, ADMET profiling, and quantum chemical analysis
Abstract
A series of novel cyclic alkene template (CAT) isosteres (CAT-0 to CAT-7) were designed and evaluated through an integrated in silico workflow combining molecular docking, density functional theory (DFT) based electronic structure analysis, ADMET prediction, CYP450 profiling, and preliminary synthetic feasibility assessment. Two biologically relevant protein targets, protein tyrosine phosphatase 1B (PTPN1) and estrogen receptor alpha (ERα/ESR1), were investigated to explore the potential biological activity profiles of the designed compounds. Docking studies were performed using the 2HNP and 3ERT crystal structures for PTPN1 and ERα, respectively. Validation of the docking protocols through reproduction of the corresponding co-crystallized ligand poses yielded RMSD values below 2 Å, supporting the reliability of the docking procedures. CAT-3, CAT-4, and CAT-7 were identified as the most promising candidates based on their predicted binding affinities across the two targets. Electronic structure analysis suggested that variations in electrostatic potential distribution and frontier orbital characteristics may contribute to differences in binding behavior within the series, supporting the isosteric design strategy. ADMET and toxicity predictions indicated generally favorable drug-like properties, with most compounds exhibiting acceptable gastrointestinal absorption and low predicted CYP450 inhibitory activity, suggesting a limited risk of CYP-mediated drug–drug interactions. However, variability in blood–brain barrier permeability and model-dependent toxicity endpoints highlights the inherent uncertainty of in silico ADMET predictions and warrants cautious interpretation of absolute values. Among the designed compounds, CAT-3 emerged as the most balanced lead candidate, combining favorable docking performance, acceptable predicted pharmacokinetic properties, and improved synthetic accessibility relative to CAT-4 and CAT-7, which, despite strong predicted affinities, present greater synthetic constraints. Its structural relationship to trodusquemine further supports its relevance as a promising scaffold. Overall, CAT-3 represents the most favorable compromise between predicted biological activity and practical feasibility within the series. Nevertheless, given the limitations of empirical scoring functions, rigid receptor approximations, and predictive ADMET models, these findings should be regarded as hypothesis-generating. Further validation through molecular dynamics simulations, MM-GBSA free energy calculations, and experimental assays will be required to confirm the predicted biological relevance of the CAT series.
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BibTeX
@misc{rouille2026silico,
title = {{In silico evaluation of novel isosteres against PTPN1 and estrogen receptor alpha: molecular docking, ADMET profiling, and quantum chemical analysis}},
author = {Lilian Rouille},
howpublished = {ChemRxiv},
year = {2026},
month = sep,
doi = {10.26434/chemrxiv.15006651/v2},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15006651/v2},
note = {CC BY},
}
RIS
TY - UNPB
TI - In silico evaluation of novel isosteres against PTPN1 and estrogen receptor alpha: molecular docking, ADMET profiling, and quantum chemical analysis
AU - Lilian Rouille
PY - 2026
DA - 2026/09/29
PB - ChemRxiv
DO - 10.26434/chemrxiv.15006651/v2
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15006651/v2
AB - A series of novel cyclic alkene template (CAT) isosteres (CAT-0 to CAT-7) were designed and evaluated through an integrated in silico workflow combining molecular docking, density functional theory (DFT) based electronic structure analysis, ADMET prediction, CYP450 profiling, and preliminary synthetic feasibility assessment. Two biologically relevant protein targets, protein tyrosine phosphatase 1B (PTPN1) and estrogen receptor alpha (ERα/ESR1), were investigated to explore the potential biological activity profiles of the designed compounds. Docking studies were performed using the 2HNP and 3ERT crystal structures for PTPN1 and ERα, respectively. Validation of the docking protocols through reproduction of the corresponding co-crystallized ligand poses yielded RMSD values below 2 Å, supporting the reliability of the docking procedures. CAT-3, CAT-4, and CAT-7 were identified as the most promising candidates based on their predicted binding affinities across the two targets. Electronic structure analysis suggested that variations in electrostatic potential distribution and frontier orbital characteristics may contribute to differences in binding behavior within the series, supporting the isosteric design strategy. ADMET and toxicity predictions indicated generally favorable drug-like properties, with most compounds exhibiting acceptable gastrointestinal absorption and low predicted CYP450 inhibitory activity, suggesting a limited risk of CYP-mediated drug–drug interactions. However, variability in blood–brain barrier permeability and model-dependent toxicity endpoints highlights the inherent uncertainty of in silico ADMET predictions and warrants cautious interpretation of absolute values. Among the designed compounds, CAT-3 emerged as the most balanced lead candidate, combining favorable docking performance, acceptable predicted pharmacokinetic properties, and improved synthetic accessibility relative to CAT-4 and CAT-7, which, despite strong predicted affinities, present greater synthetic constraints. Its structural relationship to trodusquemine further supports its relevance as a promising scaffold. Overall, CAT-3 represents the most favorable compromise between predicted biological activity and practical feasibility within the series. Nevertheless, given the limitations of empirical scoring functions, rigid receptor approximations, and predictive ADMET models, these findings should be regarded as hypothesis-generating. Further validation through molecular dynamics simulations, MM-GBSA free energy calculations, and experimental assays will be required to confirm the predicted biological relevance of the CAT series.
ER -