Performance and Its Limits in Rigid Body Protein-Protein Docking

Desta, Israel; Porter, Kathryn A.; Xia, Bing; Kozakov, Dima; Vajda, Sándor

doi:10.1016/j.str.2020.06.006

Cited by 464 publications

(335 citation statements)

References 55 publications

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“…S11 B). To test this structural hypothesis, two docking studies were performed using the popular protein-docking webserver Cluspro (v.2) [ 105 , 106 ]: (a) docking of angiotensin II vs. ACE2 and (b) docking of angiotensin II vs. the RBD Spike –ACE2 binary PPI complex.…”

Section: Resultsmentioning

confidence: 99%

Plausible blockers of Spike RBD in SARS-CoV2—molecular design and underlying interaction dynamics from high-level structural descriptors

et al. 2021

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COVID-19 is characterized by an unprecedented abrupt increase in the viral transmission rate (SARS-CoV-2) relative to its pandemic evolutionary ancestor, SARS-CoV (2003). The complex molecular cascade of events related to the viral pathogenicity is triggered by the Spike protein upon interacting with the ACE2 receptor on human lung cells through its receptor binding domain (RBD Spike ). One potential therapeutic strategy to combat COVID-19 could thus be limiting the infection by blocking this key interaction. In this current study, we adopt a protein design approach to predict and propose non-virulent structural mimics of the RBD Spike which can potentially serve as its competitive inhibitors in binding to ACE2. The RBD Spike is an independently foldable protein domain, resilient to conformational changes upon mutations and therefore an attractive target for strategic re-design. Interestingly, in spite of displaying an optimal shape fit between their interacting surfaces (attributed to a consequently high mutual affinity), the RBD Spike –ACE2 interaction appears to have a quasi-stable character due to a poor electrostatic match at their interface. Structural analyses of homologous protein complexes reveal that the ACE2 binding site of RBD Spike has an unusually high degree of solvent-exposed hydrophobic residues, attributed to key evolutionary changes, making it inherently “reaction-prone.” The designed mimics aimed to block the viral entry by occupying the available binding sites on ACE2, are tested to have signatures of stable high-affinity binding with ACE2 (cross-validated by appropriate free energy estimates), overriding the native quasi-stable feature. The results show the apt of directly adapting natural examples in rational protein design, wherein, homology-based threading coupled with strategic “hydrophobic ↔ polar” mutations serve as a potential breakthrough. Graphical Abstract Supplementary Information The online version contains supplementary material available at 10.1007/s00894-021-04779-0.

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Section: Resultsmentioning

confidence: 99%

Plausible blockers of Spike RBD in SARS-CoV2—molecular design and underlying interaction dynamics from high-level structural descriptors

et al. 2021

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“…Considering the fact that rigid docking has some limitations as the protein is kept rigid [ 37 , 38 ], the accuracy of its results has to be further evaluated. The induced-fit docking module of Schrödinger was utilized to accomplish induced-fit docking [ 39 , 40 ].…”

Section: Methodsmentioning

confidence: 99%

Evaluation of potential anti-RNA-dependent RNA polymerase (RdRP) drugs against the newly emerged model of COVID-19 RdRP using computational methods

Poustforoosh

Hashemipour

Tüzün

et al. 2021

Biophysical Chemistry

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Introduction Despite all the efforts to treat COVID-19, no particular cure has been found for this virus. Since developing antiviral drugs is a time-consuming process, the most effective approach is to evaluate the approved and under investigation drugs using in silico methods. Among the different targets within the virus structure, as a vital component in the life cycle of coronaviruses, RNA-dependent RNA polymerase (RdRP) can be a critical target for antiviral drugs. The impact of the existence of RNA in the enzyme structure on the binding affinity of anti-RdRP drugs has not been investigated so far. Methods In this study, the potential anti-RdRP effects of a variety of drugs from two databases (Zinc database and DrugBank) were evaluated using molecular docking. For this purpose, the newly emerged model of COVID-19 (RdRP) post-translocated catalytic complex (PDB ID: 7BZF ) that consists of RNA was chosen as the target. Results The results indicated that idarubicin (IDR), a member of the anthracycline antibiotic family, and fenoterol (FNT), a known beta-2 adrenergic agonist drug, tightly bind to the target enzyme and could be used as potential anti-RdRP inhibitors of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). These outcomes revealed that due to the ligand-protein interactions, the presence of RNA in this structure could remarkably affect the binding affinity of inhibitor compounds. Conclusion In silico approaches, such as molecular docking, could effectively address the problem of finding appropriate treatment for COVID-19. Our results showed that IDR and FNT have a significant affinity to the RdRP of SARS-CoV-2; therefore, these drugs are remarkable inhibitors of coronaviruses.

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“…In order to assess the validity of the initial model, we performed a redocking experiment using a known crystal structure of the EBOV GPcl–NPC1 complex (PDB ID: 5F1B). Even though this structure did not have any apparent steric hindrances or other unfavorable interactions, the redocking study using three sophisticated tools (MOE, ZDOCK [ 38 ], and ClusPro [ 39 ]) did not generate the near-native structure (i.e., near-crystal structure). Protein–protein docking simulations sometimes fail to reveal the correct structures.…”

Section: Discussionmentioning

confidence: 99%

Structural Insights into the Interaction of Filovirus Glycoproteins with the Endosomal Receptor Niemann-Pick C1: A Computational Study

Igarashi

Hirokawa

Takadate

et al. 2021

Viruses

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Filoviruses, including marburgviruses and ebolaviruses, have a single transmembrane glycoprotein (GP) that facilitates their entry into cells. During entry, GP needs to be cleaved by host proteases to expose the receptor-binding site that binds to the endosomal receptor Niemann-Pick C1 (NPC1) protein. The crystal structure analysis of the cleaved GP (GPcl) of Ebola virus (EBOV) in complex with human NPC1 has demonstrated that NPC1 has two protruding loops (loops 1 and 2), which engage a hydrophobic pocket on the head of EBOV GPcl. However, the molecular interactions between NPC1 and the GPcl of other filoviruses remain unexplored. In the present study, we performed molecular modeling and molecular dynamics simulations of NPC1 complexed with GPcls of two ebolaviruses, EBOV and Sudan virus (SUDV), and one marburgvirus, Ravn virus (RAVV). Similar binding structures were observed in the GPcl–NPC1 complexes of EBOV and SUDV, which differed from that of RAVV. Specifically, in the RAVV GPcl–NPC1 complex, the tip of loop 2 was closer to the pocket edge comprising residues at positions 79–88 of GPcl; the root of loop 1 was predicted to interact with P116 and Q144 of GPcl. Furthermore, in the SUDV GPcl–NPC1 complex, the tip of loop 2 was slightly closer to the residue at position 141 than those in the EBOV and RAVV GPcl–NPC1 complexes. These structural differences may affect the size and/or shape of the receptor-binding pocket of GPcl. Our structural models could provide useful information for improving our understanding the differences in host preference among filoviruses as well as contributing to structure-based drug design.

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Performance and Its Limits in Rigid Body Protein-Protein Docking

Cited by 464 publications

References 55 publications

Plausible blockers of Spike RBD in SARS-CoV2—molecular design and underlying interaction dynamics from high-level structural descriptors

Plausible blockers of Spike RBD in SARS-CoV2—molecular design and underlying interaction dynamics from high-level structural descriptors

Evaluation of potential anti-RNA-dependent RNA polymerase (RdRP) drugs against the newly emerged model of COVID-19 RdRP using computational methods

Structural Insights into the Interaction of Filovirus Glycoproteins with the Endosomal Receptor Niemann-Pick C1: A Computational Study

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