Novel Thiourea and Oxime Ether Isosteviol-Based Anticoagulants: MD Simulation and ADMET Prediction
<p>The crystal structure of <span class="html-italic">H. sapiens</span> FXa (red) in complex with a calcium cation (yellow) and an inhibitor; PDB code: 2P16. The inset shows the binding pocket, with key residues highlighted. The binding pocket comprises four subpockets: S1 (constructed by C191, Q192, D194, and I227), S2 (C219), S3 (E147 and G218), and S4 (Y99, F174, W215, G216, and E217).</p> "> Figure 2
<p>Structures of complexes between ISV derivatives and FXa (red) obtained through docking (<b>A</b>–<b>I</b>). These structures served as the initial configurations for the subsequent MD simulations.</p> "> Figure 3
<p>RMSD values of protein backbone (red) and ligand (blue) for the simulation of an FXa complex with different ligands (<b>A</b>–<b>I</b>). While the RMSD for the protein backbone remains stable with consistently small values across all simulations, the RMSD of the ligand varies between simulations, indicating distinct stability levels of the complexes.</p> "> Figure 4
<p>The distance between the CoM of the ligand and the CoM of FXa throughout the simulations (<b>A</b>–<b>I</b>). Typically, the distance remains around 15 to 20 Å, except for the FXa complex with E04. In this case, after 15 ns, the distance increases rapidly, stabilizing at 25 Å. This observation implies the dissociation of the ligand and its potential rebinding at a different site.</p> "> Figure 5
<p>The RMSD changes of amino acids forming the binding pocket (Y99, E147, F174, C191, Q192, D194, W215, G216, E217, G218, C219, and I227) (<b>A</b>–<b>I</b>). The RMSD for FXa complexes with E10, E20, and E21 remains relatively stable, with low values ranging from 2 to 3 Å. In contrast, other complexes show larger RMSD changes, indicating diverse mobility of the ligand-binding site, dependent on the specific type of ligand bound.</p> "> Figure 6
<p>Representative ligand conformations bound to FXa. Conformations were chosen through ligand clustering using the GROMOS algorithm with a cutoff of 1.0 Å, based on frames sampled every 100 ps. Conformations found in less than 5% of frames are not shown for clarity. (<b>A</b>): E10, (<b>B</b>): E15, (<b>C</b>): E20, and (<b>D</b>): E24.</p> "> Figure 7
<p>Snapshots from MD simulations for the most representative conformations of the ligands shown in <a href="#pharmaceuticals-17-00163-f006" class="html-fig">Figure 6</a>. The stick representation depicts the side chains of key residues and ligands. Hydrogen bonds are shown with dashed lines. (<b>A</b>): E10, (<b>B</b>): E15, (<b>C</b>): E20, and (<b>D</b>): E24.</p> "> Figure 8
<p>Chemical structures of FDA-approved FXa inhibitors.</p> ">
Abstract
:1. Introduction
2. Results and Discussion
2.1. Molecular Dynamic (MD) Simulation and Analysis
2.1.1. ISV Derivative Complexes with FXa Exhibit Variable Stability
2.1.2. ISV Derivatives Exhibit Different Conformational Dynamics
2.1.3. ISV Derivatives Exhibit a Similar Pattern of Interaction to FDA-Approved FXa Inhibitors
2.2. ADMET prediction
2.3. Limitations of the Present Study
3. Materials and Methods
3.1. MD Simulation
3.2. ADMET Properties Prediction
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Ligand | Structure | IUPAC Name | Binding Free Energy [kcal/mol] | Molar Mass [g/mol] |
---|---|---|---|---|
E01 | ethyl (4R,4aS,6aR,9S,11aR,11bS,E)-8-(2-((3-chloro-4-fluorophenyl)carbamothioyl)hydrazineylidene)-4,9,11b-trimethyltetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate | −8.8 | 548.16 | |
E04 | ethyl (4R,4aS,6aR,9S,11aR,11bS,E)-8-(2-((4-chloro-3-fluorophenyl)carbamothioyl)hydrazineylidene)-4,9,11b-trimethyltetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate | −8.5 | 548.16 | |
E10 | ethyl (4R,4aS,6aR,9S,11aR,11bS,E)-4,9,11b-trimethyl-8-(2-((4-(oxazol-5-yl)phenyl)carbamothioyl)hydrazineylidene)tetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate | −8.8 | 562.77 | |
E15 | ethyl (4R,4aS,6aR,9S,11aR,11bS,E)-8-(((2,5-dichlorothiophen-3-yl)methoxy)imino)-4,9,11b-trimethyltetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate | −8.3 | 526.56 | |
E20 | ethyl (4R,4aS,6aR,9S,11aR,11bS,E)-4,9,11b-trimethyl-8-(((5-(trifluoromethyl)furan-2-yl)methoxy)imino)tetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate | −8.1 | 509.60 | |
E21 | ethyl (4R,4aS,6aR,9S,11aR,11bS,E)-4,9,11b-trimethyl-8-(((2-(trifluoromethyl)oxazol-4-yl)methoxy)imino)tetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate | −8.3 | 510.59 | |
E23 | ethyl (4R,4aS,6aR,9S,11aR,11bS,E)-4,9,11b-trimethyl-8-(((5-(trifluoromethyl)thiophen-3-yl)methoxy)imino)tetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate | −8.1 | 525.67 | |
E24 | ethyl (4R,4aS,6aR,9S,11aR,11bS,E)-8-(((4-fluorothiophen-3-yl)methoxy)imino)-4,9,11b-trimethyltetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate | −8.2 | 475.66 | |
E25 | ethyl (4R,4aS,6aR,9S,11aR,11bS,E)-4,9,11b-trimethyl-8-(((1-methyl-3-(trifluoromethyl)-1H-thieno[2,3-c]pyrazol-5-yl)methoxy)imino)tetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate | −8.2 | 579.72 |
Docking Pose | Conformation from MD Simulation | ||
---|---|---|---|
First Cluster | Second Cluster | Third Cluster | |
E10 | 1.21 Å | - | - |
E15 | 1.63 Å | 0.44 Å | - |
E20 | 1.06 Å | 1.84 Å | 1.67 Å |
E24 | 0.45 Å | - | - |
Complexes | Hydrogen Bonds | ||||
---|---|---|---|---|---|
Donor | Acceptor | Occupancy [%] | Distance ± SD [Å] | Angle ± SD [°] | |
E10 | E10 (N3) | G216 (O) | 22.42 | 3.00 ± 0.32 | 28.04 ± 11.27 |
E15 | G216 (N) | E15 (N) | 28.63 | 4.22 ± 0.85 | 20.37 ± 11.18 |
Y99 (N) | E15 (O1) | 26.23 | 9.60 ± 5.23 | 40.26 ± 23.62 | |
E20 | - | - | - | - | - |
E24 | G216 (N) | E24 (N) | 40.10 | 3.56 ± 0.32 | 16.1 ± 7.93 |
Ligand | Hydrophobic Interactions | ||
---|---|---|---|
Y99 | F174 | W215 | |
E10 | 96.94% | 88.55% | 99.89% |
E15 | 99.56% | 57.40% | 99.74% |
E20 | 99.96% | 26.10% | 99.98% |
E24 | 99.01% | 81.44% | 99.98% |
Compound | Molecular Weight | Num. Rotatable Bonds | Num. H-Bond Acceptors | Num. H-Bond Donors | TPSA [Ų] 1 | Consensus Log Po/w | Lipinski | Bioavailability Score | Water Solubility [log mol/L] | Synthetic Accessibility | Intestinal Absorption [% Absorbed] | P-Glycoprotein Substrate | VDss 2 [log L/kg] | BBB Permeability 3 [log BB] | CYP2D6 Substrate | CYP2D6 Inhibitor | CYP3A4 Substrate | CYP3A4 Inhibitor | CYP1A2 Inhibitor | CYP2C19 Inhibitor | CYP2C9 Inhibitor | Total Clearance [log ml/min/kg] | AMES 4 Toxicity | Max. Tolerated Dose [log mg/kg/day] | Oral Rat Chronic Toxicity [0.644] | Hepatotoxicity |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
E01 | 548.16 | 7 | 4 | 2 | 94.81 | 6.69 | No | 0.17 | −5.198 | 6.63 | 92.59 | Yes | −0.211 | −0.233 | No | No | Yes | Yes | No | No | No | −0.711 | No | −0.264 | 0.644 | No |
E04 | 548.16 | 7 | 4 | 2 | 94.81 | 6.70 | No | 0.17 | −5.322 | 6.67 | 92.56 | Yes | −0.202 | −0.233 | No | No | Yes | Yes | No | No | No | −0.712 | No | −0.243 | 0.627 | No |
E10 | 562.77 | 8 | 5 | 2 | 120.84 | 6.01 | No | 0.17 | −5.463 | 6.96 | 94.29 | Yes | 0.377 | −0.086 | No | No | Yes | No | No | No | No | −0.682 | No | −0.02 | 0.356 | No |
E15 | 526.56 | 6 | 4 | 0 | 76.13 | 7.38 | No | 0.17 | −5.792 | 6.78 | 94.58 | Yes | −0.081 | −0.13 | No | No | Yes | No | No | No | No | −0.247 | No | 0.746 | 0.481 | No |
E20 | 509.60 | 7 | 8 | 0 | 61.03 | 6.52 | No | 0.17 | −5.917 | 6.90 | 96.36 | Yes | 0.035 | −0.195 | No | No | Yes | No | No | No | No | −0.107 | No | 0.257 | 0.711 | No |
E21 | 510.59 | 7 | 9 | 0 | 73.92 | 5.96 | No | 0.17 | −5.623 | 6.69 | 96.81 | Yes | −0.19 | −0.949 | No | No | Yes | Yes | No | No | No | −0.093 | No | 0.129 | 0.806 | No |
E23 | 525.67 | 7 | 7 | 0 | 76.13 | 7.24 | No | 0.17 | −5.673 | 6.91 | 94.42 | Yes | −0.177 | −0.12 | No | No | Yes | No | No | No | No | −0.363 | No | 0.523 | 0.588 | No |
E24 | 475.66 | 6 | 5 | 0 | 76.13 | 6.39 | Yes | 0.55 | −5.248 | 6.71 | 96.60 | No | −0.232 | −0.196 | No | No | Yes | No | No | No | No | −0.249 | No | 0.643 | 0.972 | No |
E25 | 579.72 | 7 | 8 | 0 | 93.95 | 7.11 | No | 0.17 | −5.509 | 7.14 | 94.72 | Yes | −0.185 | −0.281 | No | No | Yes | Yes | No | No | No | −0.331 | No | 0.379 | 0.54 | No |
R 5 | 435.88 | 6 | 5 | 1 | 116.42 | 2.29 | Yes | 0.55 | −4.382 | 3.63 | 92.80 | Yes | −0.687 | −1.022 | No | No | Yes | Yes | No | Yes | Yes | 0.296 | Yes | −0.232 | 1.125 | Yes |
A 6 | 459.50 | 5 | 5 | 1 | 110.76 | 2.30 | Yes | 0.55 | −4.181 | 3.48 | 88.96 | Yes | −0.14 | −0.985 | No | No | Yes | Yes | No | Yes | Yes | 0.247 | No | −0.119 | 1.276 | Yes |
E 7 | 548.06 | 10 | 7 | 3 | 164.87 | 1.35 | No | 0.17 | −3.377 | 5.04 | 72.09 | Yes | −0.243 | −1.082 | No | No | No | Yes | No | No | No | 0.474 | No | 0.109 | 2.471 | Yes |
B 8 | 451.91 | 9 | 5 | 3 | 107.41 | 3.22 | Yes | 0.55 | −4.313 | 3.05 | 76.59 | Yes | −0.08 | −1.276 | No | No | Yes | Yes | No | Yes | Yes | 0.257 | No | 0.685 | 1.181 | Yes |
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Gackowski, M.; Jędrzejewski, M.; Medicharla, S.S.; Kondabala, R.; Madriwala, B.; Mądra-Gackowska, K.; Studzińska, R. Novel Thiourea and Oxime Ether Isosteviol-Based Anticoagulants: MD Simulation and ADMET Prediction. Pharmaceuticals 2024, 17, 163. https://doi.org/10.3390/ph17020163
Gackowski M, Jędrzejewski M, Medicharla SS, Kondabala R, Madriwala B, Mądra-Gackowska K, Studzińska R. Novel Thiourea and Oxime Ether Isosteviol-Based Anticoagulants: MD Simulation and ADMET Prediction. Pharmaceuticals. 2024; 17(2):163. https://doi.org/10.3390/ph17020163
Chicago/Turabian StyleGackowski, Marcin, Mateusz Jędrzejewski, Sri Satya Medicharla, Rajesh Kondabala, Burhanuddin Madriwala, Katarzyna Mądra-Gackowska, and Renata Studzińska. 2024. "Novel Thiourea and Oxime Ether Isosteviol-Based Anticoagulants: MD Simulation and ADMET Prediction" Pharmaceuticals 17, no. 2: 163. https://doi.org/10.3390/ph17020163