Recognition of Potential COVID-19 Drug Treatments through the Study of Existing Protein–Drug and Protein–Protein Structures: An Analysis of Kinetically Active Residues
<p>Chloroquine and its target proteins. Images on the left depict chloroquine bound to the cofactor binding site of <span class="html-italic">Plasmodium falciparum</span> lactate dehydrogenase (pdb id 1cet). Images on the right depict chloroquine bound to saposin B (pdb id 4v2o). (<b>a</b>) Lactate dehydrogenase is depicted as a blue ribbon, self-adjustable Gaussian network model (SAGNM) predictions are yellow and chloroquine green atoms. (<b>b</b>) Lactate dehydrogenase is depicted as a transparent hydrophobic surface (chain is visible as ribbon inside surface). SAGNM predictions are depicted as yellow atoms and chloroquine as green atoms. (<b>c</b>) Lactate dehydrogenase is depicted as an opaque hydrophobic surface and chloroquine as green balls and sticks. (<b>d</b>) The inset shows chloroquine within the hydrophobic pocket. (<b>e</b>) Saposin B chains are depicted as blue (chain A), pink (chain B), and red (chain C) ribbons. SAGNM predictions are depicted as blue, pink, and red atoms. Chloroquine molecules are shown as green atoms. (<b>f</b>) Saposin B is depicted as a transparent hydrophobic surface. SAGNM predictions are depicted as yellow atoms and chloroquine green atoms. (<b>g</b>) Saposin B is depicted as an opaque hydrophobic surface and chloroquine as green balls and sticks. (<b>h</b>) The two insets show chloroquine molecules within the hydrophobic pockets on the surface of the saposin B trimer. The figure is produced with the UCSF Chimera program [<a href="#B58-biomolecules-10-01346" class="html-bibr">58</a>].</p> "> Figure 2
<p>Ivermectin and its target protein, human glycine receptor alpha-3 (pdb id 5vdh). (<b>a</b>) Five pentamer chains (A to E) are represented as ribbons. Ivermectin is represented via green atoms. Glycine molecules are brown and represented as atoms, and 7C6 molecules are represented as purple atoms. (<b>b</b>) Chain A from human glycine receptor Alpha-3 is represented as a blue ribbon. SAGNM predictions are depicted as yellow atoms. Ivermectin is represented via green atoms. The glycine molecule is brown and represented as spherical atoms. The 7C6 molecule is represented as purple atoms. (<b>c</b>) Chain A from human glycine receptor alpha-3 is depicted as a transparent hydrophobic surface. SAGNM predictions are yellow, glycine molecule is represented as brown, 7C6 molecule as purple, and ivermectin as green atoms. (<b>d</b>) Chain A from human glycine receptor alpha-3 is depicted as an opaque hydrophobic surface. The glycine molecule is represented as brown balls and sticks, the 7C6 molecule is represented as purple, and ivermectin as green balls and sticks. (<b>e</b>) The three insets show glycine, 7C6, and ivermectin molecules inside the hydrophobic pockets on the surface of the chain A of human glycine receptor alpha-3. The figure is produced with the VMD and UCSF Chimera programs [<a href="#B58-biomolecules-10-01346" class="html-bibr">58</a>,<a href="#B59-biomolecules-10-01346" class="html-bibr">59</a>].</p> "> Figure 3
<p>Remdesivir bound to the primer RNA inside the central channel of SARS-CoV-2 RNA-dependent RNA polymerase (RdRp), NSP12 (pdb id 7bv2 described in [<a href="#B12-biomolecules-10-01346" class="html-bibr">12</a>]). (<b>a</b>) Three RNA polymerase chains, NSP 12, NSP7, and NSP8, are represented as blue, cyan, and dark cyan ribbons. Remdesivir is represented as green atoms and pyrophosphate as dark green atoms. The dashed lines represent protein segments missing from the deposited structure. (<b>b</b>) The same structure rotated approximately 180° around the vertical axis. (<b>c</b>) Remdesivir and pyrophosphate inside the binding pocket, surrounded by the yellow SAGNM predictions (left), and inside the pocket with contact residues colored by hydrophobicity.</p> "> Figure 4
<p>Comparative analysis of hepatitis C virus (HCV) (pdb id 4wtg, chain A, left) bound to sofosbuvir, and COVID-19 RNA directed RNA polymerase (RdRp, pdb id 6m71, chain A, right). (<b>a</b>) HCV RNA-directed RNA polymerase is depicted as a blue ribbon, RNA is purple, and sofosbuvir is a green molecule (full atom representation). (<b>b</b>) HCV RdRp is represented as a transparent hydrophobic surface, SAGNM predictions are yellow and sofosbuvir is represented via green atoms. (<b>c</b>) HCV RdRp is represented as an opaque hydrophobic surface, and sofosbuvir is represented via green sticks. (<b>d</b>) The inset shows sofosbuvir inside the polymerase catalytic core. (<b>e</b>) HCV RdRp (blue ribbon) structurally aligned with COVID-19 RdRp (light blue ribbon). Sofosbuvir is a green molecule inside the HCV RdRp catalytic core. (<b>f</b>) COVID-19 RdRp as a light blue ribbon. SAGNM predictions are dark yellow atoms. Sofosbuvir is a green molecule inside the catalytic core. The position stems from the structurally aligned HCV RdRp. (<b>g</b>) COVID-19 RdRp as hydrophobically colored atoms (residues hydrophobicities). Sofosbuvir is a green molecule inside the catalytic core. The position stems from the structurally aligned HCV RdRp. With COVID-19 RNA polymerase, sofosbuvir’s position corresponds to the position it has when bound to HCV RNA polymerase.</p> "> Figure 5
<p>COVID-19 RNA directed RNA polymerase with cofactors NSP7 and NSP8 (pdb id 6m71). The NSP 12 chain is cyan, and its SAGNM predictions are yellow. The NSP 7 chain is pink and its SAGNM predictions are purple. The NSP 8 chain is orange and SAGNM predictions are dark red. The dashed lines represent segments missing from the coordinates file.</p> "> Figure 6
<p>Boceprevir and its target protein COVID-19 (SARS-CoV-2) main protease (pdb id 6wnp). (<b>a</b>) COVID-19 Main protease is depicted as a blue ribbon, SAGNM predictions are yellow, and boceprevir as green atoms. (<b>b</b>) COVID-19 main protease is depicted as a transparent hydrophobic surface, SAGNM predictions are yellow, and chloroquine is a green molecule. (<b>c</b>) COVID-19 main protease is depicted as an opaque hydrophobic surface, and chloroquine is depicted via green balls and sticks. (<b>d</b>) The inset shows boceprevir inside the binding pocket.</p> "> Figure 7
<p>D-ornithine and its target protein <span class="html-italic">Trypanosoma brucei</span> ornithine decarboxylase (pdb id 1njj). (<b>a</b>) Ornithine decarboxylase chains A (red) and B (blue) are depicted as ribbons, with D-ornithine and G-418 as green and dark green molecules, respectively. (<b>b</b>) Ornithine decarboxylase chains A and B are depicted as hydrophobicity surface, with D-ornithine and G-418 as green and dark green molecules, respectively. (<b>c</b>) Ornithine decarboxylase chain A depicted as a transparent hydrophobicity surface, with SAGNM predictions are yellow atoms, and with D-ornithine and G-418 as green and dark green molecules. (<b>d</b>) D-ornithine and G-418 molecules depicted as colored bonds and sticks, correspondingly to the atom type and inside pockets on the surface of ornithine decarboxylase.</p> "> Figure 8
<p>SARS spike glycoprotein chain B RBD bound to the angiotensin-converting enzyme 2 (ACE2) receptor (pdb id 6cs2) in comparison to COVID-19 spike glycoprotein chain A RBD bound to the ACE2 receptor (pdb id 6m0j). (<b>a</b>) The ACE2 receptor is represented via blue atoms and its SAGM predictions are yellow atoms. SARS spike glycoprotein is represented via red atoms, and its SAGNM predictions and green atoms. (<b>b</b>) The ACE2 receptor is represented as a blue ribbon, and its SAGM predictions are yellow atoms. SARS spike glycoprotein is the red ribbon, and its SAGNM predictions and green atoms. (<b>c</b>) Contact areas for both chains are represented as hydrophobicity surfaces. The contact chains in each case are shown as ribbons, and predictions are represented via Cα atoms only. (<b>d</b>) The ACE2 receptor is represented via blue atoms, and its SAGM predictions are yellow atoms. COVID-19 spike glycoprotein is represented via red atoms, and its SAGNM predictions and green atoms. (<b>e</b>) The ACE2 receptor is represented as a blue ribbon, and its SAGM predictions are yellow atoms. COVID-19 spike glycoprotein is the red ribbon, and its SAGNM predictions are green atoms. (<b>f</b>) Contact areas for both chains are represented as hydrophobic surfaces. The contact chains in each case are shown as ribbons, and predictions are represented via Cα atoms only.</p> "> Figure 9
<p>SARS-CoV spike glycoprotein (Chain B, pdb id 6nb6) with glycans (NAG, BMA, MAN) bound to it. (<b>a</b>) Ribbon-like representation of SARS spike glycoprotein. The SAGNM predictions are yellow atoms. BMA molecules are represented via purple atoms. MAN molecules are represented via orange atoms. NAG molecules are represented via green atoms. Cyan bars represent missing glycoprotein segments. Circles represent areas where the SAGNM predictions recognize real binding spots. (<b>b</b>) SARS spike glycoprotein is depicted via hydrophobicity colored atoms. Glycans (NAG, BMA, MAN) are represented via colored bonds (same colors as above). (<b>c</b>) SARS spike glycoprotein is depicted via transparent hydrophobicity colored atoms. Glycans (NAG, BMA, MAN) are represented via colored bonds (same colors as above). The SAGNM predictions are yellow atoms. Glycans (NAG, BMA, MAN) are represented via colored atoms.</p> "> Figure 10
<p>Receptor binding domain (RBD) of SARS-CoV spike glycoprotein (chain A, pdb id 6nb6) with the human neutralizing S230 antibody FAB fragment. (<b>a</b>) SARS-CoV RBD (blue, chain A) with heavy (green, H, and I) and light (red, L, and M) chains. Predictions are cyan (SARS), yellow (S230 light), and light green (S230 heavy). (<b>b</b>) Hydrophobic surface of SARS RBD bound to S230 (chains H and L). (<b>c</b>) Transparent hydrophobic surface of SARS RBD and S230 (chains H and L) with predictions.</p> ">
Abstract
:1. Introduction
2. Methods and Materials
- Step 1:
- Calculate the number of fast modes that correspond to the top 10% of the eigenvalues range.
- Step 2:
- Calculate the weighted sum (Equation (1)) and spread the influence of hot residues to sequential and spatial neighbors.
- Step 3a:
- If the overall percent of predictions is larger than a previously set value (for example, if the percent of predictions is larger than 30% of the total number of residues), the SAGNM procedure reduces the number of fast modes by one and goes to Step 2.
- Step 3b:
- If the percent of predictions is too small (e.g., less than 15% of all residues), the SAGNM procedure increases the number of fast modes by one and goes to Step 2.
3. Results
3.1. Chloroquine
3.2. Ivermectin
3.3. Remdesivir
3.4. Sofosbuvir
3.5. Boceprevir
3.6. Eflornithine
3.7. Spike Glycoproteins and Their Interactions
3.7.1. ACE2 Binding Patterns to SARS and COVID-19 Spike Glycoproteins
3.7.2. SARS-CoV Spike Glycoprotein and Glycans
3.7.3. SARS Spike Glycoprotein RBD and Human Antibody Fragment
4. Discussion and Conclusions
Supplementary Materials
Funding
Acknowledgments
Conflicts of Interest
References
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Drug | Indication | Dosage in Individuals Aged ≥ 12 Years | Effectiveness | Side Effects | Precautions in Patients with Complications | |||
---|---|---|---|---|---|---|---|---|
Cardio-Pulmonary | Renal | Hepatic | Retinal[M1] | |||||
Chloroquine | Treatment Prevention | 500–600 mg weekly | Malaria, Amebiasis, Porphyria Cutanea Tarda | Serious | Yes | Yes | Yes | Yes |
Ivermectin | Treatment Prevention | 3–15 mg once | Parasitic infestations | Mild/Serious | No | Yes | Yes | No |
Remdesivir | Treatment | 100–200 mg daily | Ebola, Marburg virus diseases | Mild | No | Yes | No | No |
Sofosbuvir | Treatment | 400 mg daily | Hepatitis-C, HIV | Mild/Moderate | Yes | Yes | Yes | Yes |
Boceprevir | Treatment | 200 mg daily | Hepatitis-C | Mild/Serious | Yes | No | Yes | Yes |
α-Difluoromethylornithine | Treatment | 300–400 mg/kg/day, cream | Trypanosomiasis, reduction of facial hair in women | Mild/Serious | No | No | Yes | No |
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Perišić, O. Recognition of Potential COVID-19 Drug Treatments through the Study of Existing Protein–Drug and Protein–Protein Structures: An Analysis of Kinetically Active Residues. Biomolecules 2020, 10, 1346. https://doi.org/10.3390/biom10091346
Perišić O. Recognition of Potential COVID-19 Drug Treatments through the Study of Existing Protein–Drug and Protein–Protein Structures: An Analysis of Kinetically Active Residues. Biomolecules. 2020; 10(9):1346. https://doi.org/10.3390/biom10091346
Chicago/Turabian StylePerišić, Ognjen. 2020. "Recognition of Potential COVID-19 Drug Treatments through the Study of Existing Protein–Drug and Protein–Protein Structures: An Analysis of Kinetically Active Residues" Biomolecules 10, no. 9: 1346. https://doi.org/10.3390/biom10091346