Design and computational evaluation of reversible covalent cathepsin S inhibitors using molecular docking, ADMET, molecular dynamics, MM/PBSA, and density functional theory
Abstract
Cathepsin S (CatS) is unique among lysosomal cathepsins in retaining significant proteolytic activity under extracellular conditions. Its extracellular activity has been implicated in tumour progression, chronic inflammation, autoimmune disorders, and cardiovascular diseases, making CatS an attractive target for the development of selective covalent inhibitors . In the present study, a series of 100 α-cyanoacrylamide derivatives was rationally designed and evaluated using computational approaches. The compounds were first assessed by rigid molecular docking. Top candidates were selected for pharmacokinetics study and initial 25 ns molecular dynamics (MD) simulations for further stability evaluation. Based on these results, Compounds F7 and F48 were subjected to density functional theory (DFT) calculations, covalent and non-covalent induced fit docking, followed by 100 ns MD simulations. Complex stability and binding behaviour were further examined using root mean square deviation (RMSD), root mean square fluctuation (RMSF), hydrogen-bond analysis, free-energy landscape analysis, per-residue energy decomposition, and molecular mechanics Poisson-Boltzman surface area (MM/PBSA) calculations. F7 consistently showed more favorable behaviour than F48 throughout the study. It maintained a stable binding mode, persistence interactions with key active site residues, and favorable accommodation of its alkyl substituent within the S2 binding pocket. These observations were supported by lower conformational fluctuations, stronger residue-level energetic contributions, and a more favorable MM/PBSA binding free energy (-33.47 kcal/mol) and than F48 (-27.72 kcal/ mol). The findings provide a molecular basis for the design of extracellularly targeted covalent CatS inhibitors and identify F7 as a suitable scaffold for further experimental investigations.
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BibTeX
@misc{hasan2026design,
title = {{Design and computational evaluation of reversible covalent cathepsin S inhibitors using molecular docking, ADMET, molecular dynamics, MM/PBSA, and density functional theory}},
author = {Yousif Sajjad Hasan},
howpublished = {ChemRxiv},
year = {2026},
month = sep,
doi = {10.26434/chemrxiv.15008514/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008514/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Design and computational evaluation of reversible covalent cathepsin S inhibitors using molecular docking, ADMET, molecular dynamics, MM/PBSA, and density functional theory
AU - Yousif Sajjad Hasan
PY - 2026
DA - 2026/09/08
PB - ChemRxiv
DO - 10.26434/chemrxiv.15008514/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008514/v1
AB - Cathepsin S (CatS) is unique among lysosomal cathepsins in retaining significant proteolytic activity under extracellular conditions. Its extracellular activity has been implicated in tumour progression, chronic inflammation, autoimmune disorders, and cardiovascular diseases, making CatS an attractive target for the development of selective covalent inhibitors . In the present study, a series of 100 α-cyanoacrylamide derivatives was rationally designed and evaluated using computational approaches. The compounds were first assessed by rigid molecular docking. Top candidates were selected for pharmacokinetics study and initial 25 ns molecular dynamics (MD) simulations for further stability evaluation. Based on these results, Compounds F7 and F48 were subjected to density functional theory (DFT) calculations, covalent and non-covalent induced fit docking, followed by 100 ns MD simulations. Complex stability and binding behaviour were further examined using root mean square deviation (RMSD), root mean square fluctuation (RMSF), hydrogen-bond analysis, free-energy landscape analysis, per-residue energy decomposition, and molecular mechanics Poisson-Boltzman surface area (MM/PBSA) calculations. F7 consistently showed more favorable behaviour than F48 throughout the study. It maintained a stable binding mode, persistence interactions with key active site residues, and favorable accommodation of its alkyl substituent within the S2 binding pocket. These observations were supported by lower conformational fluctuations, stronger residue-level energetic contributions, and a more favorable MM/PBSA binding free energy (-33.47 kcal/mol) and than F48 (-27.72 kcal/ mol). The findings provide a molecular basis for the design of extracellularly targeted covalent CatS inhibitors and identify F7 as a suitable scaffold for further experimental investigations.
ER -