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. 2025 May 14;20(5):e0323699.
doi: 10.1371/journal.pone.0323699. eCollection 2025.

Design, optimization, and ADMET evaluation of S11a-0000168202: A promising LIMK1 inhibitor for gastric cancer treatment

Guojun Li  1 , Jionghuang Chen  2 , Rui Chen  3 , Weihua Yu  2
Affiliations

Design, optimization, and ADMET evaluation of S11a-0000168202: A promising LIMK1 inhibitor for gastric cancer treatment

Guojun Li et al. PLoS One. .

Abstract

This study focuses on the development and optimization of S11a-0000168202, a novel LIMK1 inhibitor with potential therapeutic applications in gastric cancer. Through scaffold hopping and structural modification of HIT100844099, S11a-0000168202 demonstrated enhanced binding stability and stronger interactions with key LIMK1 residues, including GLU-414, ILE-416, and HIS-464. Molecular dynamics simulations and MMGBSA analyses confirmed the compound's stability, while ADMET evaluation revealed favorable properties such as moderate lipophilicity, good human intestinal absorption, and low P-glycoprotein inhibition. Despite the promising computational results, the lack of experimental validation remains a limitation. Future studies should focus on in vitro and in vivo testing to confirm S11a-0000168202's efficacy, pharmacokinetics, and safety. This compound holds significant potential as a therapeutic agent for LIMK1-targeted gastric cancer treatment.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig 1
Fig 1. Evaluation of re-docking accuracy across different docking precision levels.
(A) Superimposition of the LIMKi3 binding conformations obtained from three different accuracy levels with the co-crystal structure. (B) Binding mode of LIMKi3 in the co-crystal state with LIMK1. (C) Binding mode of LIMKi3 with LIMK1 obtained from HTVS accuracy calculation. (D) Binding mode of LIMKi3 with LIMK1 obtained from SP accuracy calculation. (E) Binding mode of LIMKi3 with LIMK1 obtained from XP accuracy calculation.
Fig 2
Fig 2. Pharmacophore features and similarity scores of different compounds.
Base feature spheres for hydrogen bond acceptors (pink), donors (blue), hydrophobes [31], and aromatic rings (orange).
Fig 3
Fig 3. Medicinal Chemistry Radar Chart.
(A) LIMKi3 (B) HIT100844099 (C) HIT103203505.
Fig 4
Fig 4. 2D Interaction Diagram of Compounds with LIMK1.
(A) LIMKi3 (B) HIT100844099 (C) HIT103203505.
Fig 5
Fig 5. Binding Stability and Free Energy Calculations of the Three Compounds.
Dynamic changes in RMSD over time: (A) LIMKi3 (B) HIT100844099 (C) HIT103203505. Dynamic changes in MMGBSA over time: (D) LIMKi3 (E) HIT100844099 (F) HIT103203505.
Fig 6
Fig 6. Interaction Analysis of the Three Compounds with LIMK1.
Dynamic changes in the number of hydrogen bonds over time: (A) LIMKi3 (B) HIT100844099 (C) HIT103203505. Impact on RMSF of LIMK1 before and after binding: (D) LIMKi3 (E) HIT100844099 (F) HIT103203505. Interaction statistics of compounds with different residues: (G) LIMKi3 (H) HIT100844099 (I) HIT103203505. Binding mode of compounds with LIMK1: (J) LIMKi3 (K) HIT100844099 (L) HIT103203505.
Fig 7
Fig 7. Post-Modifications Evaluation and Interaction Analysis of S11a-0000168202.
(A) Differences before and after scaffold hopping of HIT100844099. (B) Medicinal Chemistry Radar Chart of S11a-0000168202. RMSF differences before and after scaffold hopping for binding with LIMK1: (C) S11a-0000168202 (D) HIT100844099. (E) Dynamic changes in RMSD of S11a-0000168202 over time. (F) Dynamic changes in MMGBSA of S11a-0000168202 over time. (G) Interaction type statistics of S11a-0000168202 with LIMK1.
Fig 8
Fig 8. Site-Directed Mutagenesis Validation of the Structure-Activity Relationship of S11a-0000168202.
Secondary structure analysis of LIMK1: (A) WT (B) T413A (C) E414A (D) I416A (E) H464A. RMSF of S11a-0000168202 bound to LIMK1 after mutations: (F) T413A (G) E414A (H) I416A (I) H464A.
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