Finding the First Potential Inhibitors of Shikimate Kinase from Methicillin Resistant Staphylococcus aureus through Computer-Assisted Drug Design
Abstract
:1. Introduction
2. Results and Discussion
2.1. Compounds Filtering
2.2. Virtual Screening
2.3. Molecular Dynamics Studies
2.4. Linear Interaction Energy
2.5. ADME-Tox Evaluation
3. Materials and Methods
3.1. Small Molecules Chemical Library
3.2. Docking Studies
3.3. Molecular Dynamics Studies
3.4. Linear Interaction Energy Calculations
3.5. ADME Properties Prediction
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Compound | Zinc ID | Structure | Docking Score (kcal/mol) | Interacting Residues (Distance Cut-Off 4.0Å) |
---|---|---|---|---|
C1 | 000737165696 | −3.905 | Arg61 2, Gly82 1, Arg120 1, 2, Arg138 1, Met14 4, Asp37 4, Glu41 4, Thr47 4, Ile48 4, Phe49 4, Phe52 4, Gly81 4, Gly83 4, Asp116 4, His119 4, Pro121 4, Asn122 4 | |
C2 | 000019366016 | −3.846 | Lys18 2, Arg61 2, Arg120 2, Arg138 2, Met14 4, Gly15 4, Lys18 4, Asp37 4, Ile48 4, Phe52 4, Phe60 4, Glu64 4, Thr80 4, Gly81 4, Gly82 4, Gly83 4, Pro121 4, Asn122 4 | |
C3 | 000653035164 S enantiomer | −3.451 | Asp35 1, Asp37 1, Arg120 1, Arg138 1, Phe13 4, Met14 4, Lys18 4, Ser19 4, Ile36 4, Glu41 4, Ile48 4, Phe52 4, Arg61 4, Ala79 4, Thr80 4, Gly81 4, Gly82 4, Gly83 4, Asp116 4, His119 4, Pro121 4, Asn122 4 | |
C4 | 000000197090 | −3.406 | Glu41 1,2, Gly82 1, Asp116 2, Arg120 1, Met14 4, Gly15 4, Thr16 4, Gly17 4, Lys18 4, Ser19 4, Asp35 4, Asp37 4, Ser38 4, Ile48 4, Pro49 4, Phe52 4, Phe60 4, Arg61 4, Ala79 4, Thr80 4, Gly81 4, Gly83 4, His119 4, Pro121 4, Asn122 4, Arg138 4 | |
C5 | 001153862505 R enantiomer | −3.286 | Lys18 2, Arg61 1, Glu64 1, Gly82 1, Arg120 3, Met14 4, Ser19 4, Asp35 4, Asp37 4, Ile48 4, Phe52 4, Phe60 4, Thr80 4, Gly81 4, Gly83 4, Ile84 4, Pro121 4, Asn122 4, Arg138 4 |
0 ns | 20 ns | 40 ns | 60 ns | 80 ns | 100 ns | |
---|---|---|---|---|---|---|
C1 | * Arg61, Gly82, Arg138 | * Gly15, Lys18 | * Gly15, Lys18, Arg61 | * Gly15, Lys18, Arg138 | * Gly15, Lys18, Arg138 | * Gly15, Lys18, Arg138 |
C2 | * Lys18, Arg61, Gly82, Arg120 Asn122, Arg138 | * Lys18, Arg61, Gly82 | * Lys18, Arg61, Gly82, Asn115 | * Lys18, Gly82, Lys126 | * Asn122, Lys 126, Arg138 | * Thr127 |
C3 | * Lys18, Asp37, Arg120, Arg138 | * Ser19, Asp35, Gly82, Arg120, Asn124 | * Ser19, Asp35, Arg120, Asn124 | * Asp35, Arg120, Ala123 | * Ser19, Asp35, Arg61 | * Ser19, Asp35, Arg120, Asn122 |
C4 | *Ser19, Glu41, Arg120 | *Glu41, Gly82 | *Glu41, Arg120 | *Asp37, Glu41 | *Glu41, Gly82 | *Ser19, Glu41 , |
Energy (Kcal/mol) | |||||
---|---|---|---|---|---|
Complex | (VLJ)Bound | (VLJ)Free | (VCL)Bound | (VCL)Free | ΔGbind kcal/mol |
SaSK-C1 | −21.39 | −5.46 | −107.92 | −70.41 | −21.62 |
SaSK-C2 | −14.45 | 1.96 | −65.15 | −160.90 | 48.41 |
SaSK-C3 | −13.93 | −4.69 | −6.74 | −8.58 | 0.8 |
SaSK-C4 | −23.25 | −14.70 | −28.31 | −43.56 | −37.47 |
C1 | C2 | C3 | C4 | |
---|---|---|---|---|
MW (g/mol) | 266.24 | 272.30 | 328.34 | 335.4 |
RB | 4 | 4 | 5 | 3 |
HBA | 9 | 8 | 7 | 6 |
HBD | 0 | 0 | 4 | 1 |
MR | 58.9 | 59.83 | 81.04 | 102.64 |
TPSA (Å2) | 124.04 | 137.64 | 134.01 | 78.88 |
cLogP | 0.47 | −2.60 | 0.68 | 2.96 |
Lipinski rules violations | 0 | 0 | 0 | 0 |
Water Solubility | ||||
LogS | −1.06 | 2.84 | −1.0 | −1.87 |
Class | Very soluble | Highly soluble | Very soluble | Very soluble |
Druglikeness | ||||
Ghose | Yes | 1 violation: WLOGP < −0.4 | 1 violation: WLOGP<-0.4 | No; 1 violation: WLOGP < −0.4 |
Veber | Yes | Yes | Yes | Yes |
Egan | Yes | 1 violation: TPSA > 131.6 | 1 violation: TPSA > 131.6 | Yes |
Muegge | Yes | 1 violation: XLOGP3 < −2 | Yes | Yes |
Bioavailability Score | 0.56 | 0.55 | 0.55 | 0.55 |
Medicinal Chemistry | ||||
PAINS | No alerts | No alerts | No alerts | No alerts |
Brenk | No alerts | 1 alert: sulfonic_acid_2 | No alerts | No alerts |
Leadlikeness | Yes | Yes | No | Yes |
Synthetic accessibility | 2.21 | 3.12 | 3.19 | 3.16 |
C1 | C2 | C3 | C4 | |
---|---|---|---|---|
BBBP | 0.0488584 | 0.0466103 | 0.037606 | 0.0466103 |
CaCo-2 (nm/s) | 4.65788 | 2.24237 | 0.373322 | 2.24237 |
HIA (%) | 64.622234 | 58.373794 | 69.411618 | 58.373794 |
MDCK (nm/s) | 1.05816 | 354.049 | 0.591682 | 354.049 |
In vitro P-glycoprotein inhibition | Non | Non | Non | Non |
PPB (%) | 65.392204 | 45.848496 | 39.567509 | 45.848496 |
Water solubility in pure water (mg/L) | 9254.72 | 2.96157e + 006 | 3141.21 | 2.96157e + 006 |
In vitro skin permeability (logKp, cm/h) | −2.71782 | −2.46455 | −4.61446 | −2.46455 |
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Rios-Soto, L.; Téllez-Valencia, A.; Sierra-Campos, E.; Valdez-Solana, M.; Cisneros-Martínez, J.; Gómez Palacio-Gastélum, M.; Castillo-Villanueva, A.; Avitia-Domínguez, C. Finding the First Potential Inhibitors of Shikimate Kinase from Methicillin Resistant Staphylococcus aureus through Computer-Assisted Drug Design. Molecules 2021, 26, 6736. https://doi.org/10.3390/molecules26216736
Rios-Soto L, Téllez-Valencia A, Sierra-Campos E, Valdez-Solana M, Cisneros-Martínez J, Gómez Palacio-Gastélum M, Castillo-Villanueva A, Avitia-Domínguez C. Finding the First Potential Inhibitors of Shikimate Kinase from Methicillin Resistant Staphylococcus aureus through Computer-Assisted Drug Design. Molecules. 2021; 26(21):6736. https://doi.org/10.3390/molecules26216736
Chicago/Turabian StyleRios-Soto, Lluvia, Alfredo Téllez-Valencia, Erick Sierra-Campos, Mónica Valdez-Solana, Jorge Cisneros-Martínez, Marcelo Gómez Palacio-Gastélum, Adriana Castillo-Villanueva, and Claudia Avitia-Domínguez. 2021. "Finding the First Potential Inhibitors of Shikimate Kinase from Methicillin Resistant Staphylococcus aureus through Computer-Assisted Drug Design" Molecules 26, no. 21: 6736. https://doi.org/10.3390/molecules26216736