Table 1.
AMDET profiling parameters and shorting criteria.
Table 2.
The ADMET analysis of the selected compounds.
Table 3.
The binding affinity of the selected compounds (Kcal/mol) and their interacting residues.
Fig 1.
Two-dimensional interactions with the selected compounds with Lasl and QscR. (A) Lasl (PDB ID 1RO5) complexed with Sulfamerazine (CID 5325), illustrating the binding mode and interaction sites. (B) Lasl complexed with Sulfaperin (CID 68933), showing the conformational arrangement of the ligand within the binding pocket. (C) Lasl complexed with Quercetin (CID 5280343), highlighting the interaction network between the protein and ligand. (D) Lasl complexed with Ginkgolide A (Ligand ID 9909368), depicting the spatial orientation of the ligand within the protein's active site. (E) QscR (PDB ID 6CC0) complexed with Sulfamerazine (CID 5325), emphasizing the key residues involved in ligand binding. (F) QscR complexed with Sulfaperin (CID 68933), showing the ligand-protein interaction pattern. (G) QscR complexed with 5-chloro-N-(4-fluorobenzyl) thiophene-2-sulfonamide (CID 893742), revealing the detailed binding interactions. (H) QscR complexed with N-(carbamoylcarbamothioyl)-2-chlorobenzamide (CID 2796468), showcasing the dual binding modes of the ligands in the protein's active site.
Fig 2.
A 3D interactions shows the binding of four ligands to Lasl (PDB ID 1RO5): Sulfamerazine (CID 5325) (Red), Sulfaperin (CID 68933) (Green), Quercetin (CID 5280343) (Yellow), and Ginkgolide A (CID 9909368) (Cyan). The binding grooves of all ligands were found to share a similar spatial arrangement, with most binding sites exhibiting a predominantly hydrophobic nature. Sulfamerazine and Sulfaperin (Red and Green) show deeper binding grooves, which facilitate stronger interactions, while Quercetin and Ginkgolide A (Yellow and Cyan) display a more balanced distribution of hydrophobic and hydrophilic residues. Despite this variation, all complexes share common interaction residues, suggesting a consistent binding mode across the ligands and supporting the idea of a shared mechanism of interaction with Lasl.
Fig 3.
The binding of four ligands to QscR (PDB ID 6CC0): Sulfamerazine (CID 5325) (Red), Sulfaperin (CID 68933) (Green), Chloro-N-(4-fluorobenzyl)thiophene-2-sulfonamide (CID 893742) (Yellow), and N-(carbamoylcarbamothioyl)-2-chlorobenzamide (CID 2796468) (Cyan). The binding grooves of all ligands are predominantly hydrophobic, with the ligands occupying deep, similar-shaped grooves that align well with the protein’s active site. Sulfamerazine and Sulfaperin (Red and Green) exhibit stronger interactions with QscR, due to their deeper binding sites, whereas Chloro-N-(4-fluorobenzyl)thiophene-2-sulfonamide and N-(carbamoylcarbamothioyl)-2-chlorobenzamide (Yellow and Cyan) demonstrate a more balanced combination of hydrophobic and hydrophilic interactions. Despite these differences, all complexes share a similar pattern of interacting residues, reinforcing the likelihood of a conserved binding mechanism across the ligands and suggesting a common target interaction for QscR.
Fig 4.
RMSD analysis of protein-ligand complexes over a 200 ns simulation. (A) Lasl complexed with Sulfamerazine (CID 5325), (B) Lasl complexed with Sulfaperin (CID 68933), (C) QscR complexed with Sulfamerazine, and (D) QscR complexed with Sulfaperin. Protein RMSD is shown in cyan, and ligand RMSD is shown in red. The X-axis represents time in nanoseconds, while the Y-axis on the left corresponds to protein RMSD in nanometers and the Y-axis on the right corresponds to ligand RMSD in nanometers.
Fig 5.
RMSF analysis of protein-ligand complexes over a 200 ns simulation. (A) Lasl complexed with Sulfamerazine (CID 5325), (B) Lasl complexed with Sulfaperin (CID 68933), (C) QscR complexed with Sulfamerazine, and (D) QscR complexed with Sulfaperin. The X-axis represents residue index, and the Y-axis corresponds to the fluctuation in nanometers. The RMSF values for both the protein and ligand are plotted to assess the flexibility and dynamic behavior of the complex.
Fig 6.
SASA analysis of protein-ligand complexes over a 200 ns simulation. Lasl complexed with Sulfamerazine (Blue), Lasl complexed with Sulfaperin (Orange), QscR complexed with Sulfamerazine (Green) and QscR complexed with Sulfaperin (Red). The graph highlights the dynamic changes in the solvent-exposed surface area of the protein backbone across the different complexes state. The x axis consists of time in nanosecond and the y axis consists of SASA value in nanometer square. Regions of a protein with high solvent-accessible surface area are typically exposed to the surrounding solvent (like water). These areas are usually on the surface of the protein or in flexible regions. They might also be involved in protein-protein interactions, ligand binding, or recognition events. Conversely, areas with low SASA are generally buried inside the protein structure and are not in direct contact with the solvent. These regions are often in the protein core, contributing to the protein's stability and folding.
Fig 7.
Radius of Gyration (Rg) analysis of protein-ligand complexes over a 200 ns (200000 s) simulation . (A) Lasl Comlexed with Sulfamerazine (Blue) and Sulfaperin (Orange), (B) QscR Complexed with Sulfamerazine (Blue) and Sulfaperin (Orange). The Rg, measured in nanometers (nm), is an indicator of the protein's compactness and structural stability over time. A smaller radius of gyration indicates a protein structure that is more tightly packed, while a larger radius of gyration denotes a structure that is more spread out or unfolded. A smaller radius of gyration signifies a denser protein structure, while a larger radius of gyration indicates a more elongated or unfolded structure.
Fig 8.
The PCA results for the four complexes indicate significant insights into their conformational states. For Lasl Comlexed with Sulfamerazine (A), the top left plot (PC1 vs. PC2) shows the data distribution with PC1 explaining 57.26% and PC2 explaining 10.16% of the variance, indicating distinct conformational states. The top right plot (PC2 vs. PC3) displays the distribution along PC2 (10.16%) and PC3 (4.38%), providing a 3D view. The bottom left plot (PC1 vs. PC3) illustrates the distribution along PC1 and PC3, while the bottom right eigenvalue rank plot shows PC1, PC2, and PC3 explaining 57.26%, 10.16%, and 4.38% of the variance, respectively. For Lasl Comlexed with Sulfaperin (B), the top left plot (PC1 vs. PC2) shows PC1 explaining 11.8% and PC2 explaining 27.32%, indicating different conformational states. The top right plot (PC2 vs. PC3) shows the distribution along PC2 and PC3, with PC3 explaining 7.8%. The bottom left plot (PC1 vs. PC3) shows the variance between PC1 and PC3, and the eigenvalue rank plot indicates PC1, PC2, and PC3 explaining 11.8%, 27.32%, and 7.8%, respectively. For QscR Complexed with Sulfamerazine (C), the top left plot (PC1 vs. PC2) shows PC1 explaining 22.18% and PC2 explaining 16.87%, indicating distinct conformational clusters. The top right plot (PC2 vs. PC3) shows the variance along PC2 and PC3, with PC3 explaining 5.09%. The bottom left plot (PC1 vs. PC3) shows the distribution along PC1 and PC3, and the eigenvalue rank plot shows PC1, PC2, and PC3 explaining 22.18%, 16.87%, and 5.09%, respectively. For QscR complexed with Sulfaperin (D), the top left plot (PC1 vs. PC2) shows PC1 explaining 27.39% and PC2 explaining 19.24%, indicating distinct conformational states. The top right plot (PC2 vs. PC3) shows the distribution along PC2 and PC3, with PC3 explaining 10.39%. The bottom left plot (PC1 vs. PC3) shows the variance along PC1 and PC3, and the eigenvalue rank plot shows PC1, PC2, and PC3 explaining 27.39%, 19.24%, and 10.39%, respectively.
Table 4.
PCA Component of different Protein ligand complex.
Fig 9.
Covariance matrices illustrate the dynamic behavior of protein-ligand complexes. (A) Lasl Protein covariance while complexed with Sulfamerazine, Show drafts Exhibits a complex pattern with significant positive and negative correlations, suggesting strong coupled motions between residues, indicative of a rigid structure. The covariance values range from -0.602 nm² to 3.48 nm². (B) Lasl Protein covariance while complexed with Sulfaperin, shows a less pronounced pattern with weaker correlations, suggesting a more flexible structure. The covariance values range from -0.197 nm² to 1.07 nm². (C) QscR Protein covariance while complexed with Sulfamerazine and (D) Sulfaperin Displays a distinct pattern with strong positive correlations along the diagonal and significant negative correlations in specific regions, indicating a relatively rigid structure with concerted residue motions. The covariance values range from -0.114 nm² to 0.377 nm² (sulfamerazine) and 0.455 nm² (Sulfaperin).
Fig 10.
RMSD and RMSF Analysis of Protein-Ligand Complexes from 200 ns Molecular Dynamics Simulations. (A-D) RMSD plots for the protein (red) and ligand (blue) of the four complexes: (A) 1ro5_5325, (B) 1ro5_68933, (C) 6cc0_5325, and (D) 6cc0_68933, showing the fluctuation of the complex over time during the simulation. (E-H) RMSF analysis for each complex, highlighting the flexibility of individual protein residues. The highest RMSF values correspond to regions of the protein that exhibit the most fluctuation, suggesting potential interaction sites for the ligand. The complexes exhibit varying degrees of flexibility, with 1ro5_68933 and 6cc0_68933 showing more stable interactions, while 6cc0_5325 exhibits higher fluctuation, especially at key binding residues.
Table 5.
Summary of EDock Docking Results for Protein-Ligand Complexes, Including Predicted Binding Sites and Docking Scores.
Fig 11.
The cluster analysis plots show the number of clusters identified at each time step during the 200 ns simulation for the four complexes. (A) represents the 1ro5_5325 complex, showing the transitions between various conformational states over time. (B) The 1ro5_68933 complex, highlighting fewer transitions and a more stable structure compared to 1ro5_5325. (C) The 6cc0_5325 complex, which exhibits a high level of conformational flexibility with frequent transitions between clusters. (D) The 6cc0_68933 complex, which maintains a moderate level of stability, with fewer transitions than 6cc0_5325 but more than 1ro5_68933. The x-axis represents time in picoseconds (ps), and the y-axis shows the cluster number at each time point, reflecting the conformational dynamics of each system.
Table 6.
ADMET Properties, Docking Scores, and MD Simulation Metrics of Lead Compounds.