Discovery of natural products to block SARS-CoV-2 S-protein interaction with Neuropilin-1 receptor: A molecular dynamics simulation approach

Alshawaf, Eman; Hammad, Maha M.; Marafie, Sulaiman K.; Ali, Hamad; Al‐Mulla, Fahd; Abubaker, Jehad; Mohammad, Anwar

doi:10.1016/j.micpath.2022.105701

Cited by 7 publications

(8 citation statements)

References 71 publications

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“…Subsequently, both the apo protein and the corresponding ligand complexes displayed a favorable stability throughout the simulation (Figure 5), with overall average values of 0.112, 0.121, 0.115, 0.119, 0.118, 0.122, 0.114, and 0.120 nm for apo‐NRP‐1, eg00229, C‐end rule, CNP0427474, CNP0429647, CNP0424372, CNP0435311 and CNP0425132 respectively (Table S1). Previous studies where inhibitors of NRP‐1 were identified reported a similar RMSD pattern, showing that the compounds stayed well bound to NRP‐1 and formed stable complexes [48,61,68] …”

Section: Resultsmentioning

confidence: 55%

“…Previous studies where inhibitors of NRP-1 were identified reported a similar RMSD pattern, showing that the compounds stayed well bound to NRP-1 and formed stable complexes. [48,61,68] Rg gives insight about the compactness of a macromolecule hence determining the folding of the macromolecule. [69][70][71] The change of the Rg over time (Figure 6) indicates the unfolding of a protein and a stable Rg depicts compactness and folding.…”

Section: Molecular Dynamics (Md) Simulationmentioning

confidence: 99%

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Computational Screening of Neuropilin‐1 Unveils Novel Potential Anti‐SARS‐CoV‐2 Therapeutics

Afiadenyo,

Adams,

Agoni

et al. 2023

Chemistry & Biodiversity

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Neuropilin 1 (NRP‐1) inhibition has shown promise in reducing the infectivity of severe acute respiratory syndrome‐coronavirus‐2 (SARS‐CoV‐2) and preventing the virus entry into nerve tissues, thereby mitigating neurological symptoms in COVID‐19 patients. In this study, we employed virtual screening, including molecular docking, Molecular Dynamics (MD) simulation, and Molecular Mechanics‐Poisson Boltzmann Surface Area (MM‐PBSA) calculations, to identify potential NRP‐1 inhibitors. From a compendium of 1930 drug‐like natural compounds, we identified five potential leads: CNP0435132, CNP0435311, CNP0424372, CNP0429647, and CNP0427474, displaying robust binding energies of ‐8.2,‐8.1,‐10.7,‐8.2, and ‐8.2 kcal/mol, respectively. These compounds demonstrated interactions with critical residues Tyr297, Trp301, Thr316, Asp320, Ser346, Thr349, and Tyr353 located within the b1 subdomain of NRP‐1. Furthermore, MD simulations and MM‐PBSA calculations affirmed the stability of the complexes formed, with average root mean square deviation, radius of gyration, and solvent accessible surface area values of 0.118 nm,1.516 nmand 88.667nm² respectively. Notably, these lead compounds were estimated to penetrate the blood‐brain barrier and displayed antiviral properties, with Pa values ranging from 0.414 to 0.779. The antagonistic effects of these lead compounds merit further investigation, as they hold the potential to serve as foundational scaffolds for the development of innovative therapeutics aimed at reducing the neuroinfectivity of SARS‐CoV‐2.

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Section: Resultsmentioning

confidence: 55%

Section: Molecular Dynamics (Md) Simulationmentioning

confidence: 99%

Computational Screening of Neuropilin‐1 Unveils Novel Potential Anti‐SARS‐CoV‐2 Therapeutics

Afiadenyo,

Adams,

Agoni

et al. 2023

Chemistry & Biodiversity

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“…One moiety (L1, L2 and L5) stabilizes upon binding, while the other moiety (L3) retains the same mobility. A recent MD study by Alshawaf et al [ 35 ] found similar RMSF profiles in NRP1-b1 when complexed with specialized metabolites 3- O -methylquercetin and esculetin. Specifically, the fluctuations in the esculetin/NRP1-b1 complex were similar to those observed in our study of the unbound form, while the 3- O -methylquercetin/NRP1-b1 complex was more similar to our complex with the peptide.…”

Section: Resultsmentioning

confidence: 89%

“…Specifically, the fluctuations in the esculetin/NRP1-b1 complex were similar to those observed in our study of the unbound form, while the 3- O -methylquercetin/NRP1-b1 complex was more similar to our complex with the peptide. Notably, the study found that 3- O -methylquercetin had a more favorable energy of interaction with NRP1-b1 than esculetin [ 35 ]. Our “bound” RMSF profile may be indicative to a state of NRP1-b1 that allows stable interactions with a ligand.…”

Section: Resultsmentioning

confidence: 99%

New Crystal Form of Human Neuropilin-1 b1 Fragment with Six Electrostatic Mutations Complexed with KDKPPR Peptide Ligand

et al. 2023

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Neuropilin 1 (NRP1), a cell-surface co-receptor of a number of growth factors and other signaling molecules, has long been the focus of attention due to its association with the development and the progression of several types of cancer. For example, the KDKPPR peptide has recently been combined with a photosensitizer and a contrast agent to bind NRP1 for the detection and treatment by photodynamic therapy of glioblastoma, an aggressive brain cancer. The main therapeutic target is a pocket of the fragment b1 of NRP1 (NRP1-b1), in which vascular endothelial growth factors (VEGFs) bind. In the crystal packing of native human NRP1-b1, the VEGF-binding site is obstructed by a crystallographic symmetry neighbor protein, which prevents the binding of ligands. Six charged amino acids located at the protein surface were mutated to allow the protein to form a new crystal packing. The structure of the mutated fragment b1 complexed with the KDKPPR peptide was determined by X-ray crystallography. The variant crystallized in a new crystal form with the VEGF-binding cleft exposed to the solvent and, as expected, filled by the C-terminal moiety of the peptide. The atomic interactions were analyzed using new approaches based on a multipolar electron density model. Among other things, these methods indicated the role played by Asp320 and Glu348 in the electrostatic steering of the ligand in its binding site. Molecular dynamics simulations were carried out to further analyze the peptide binding and motion of the wild-type and mutant proteins. The simulations revealed that specific loops interacting with the peptide exhibited mobility in both the unbound and bound forms.

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“…Small-molecule inhibitors of the S-protein of SARS-CoV-2 may bind to NRP1 (22). In silico analysis has revealed that natural product small molecules that interfere with SARS-CoV-2 binding to NRP1 are potential candidate novel antiviral agents (23)(24)(25)(26). Folic acid, leucovorin and alimemazine may have the potential to prevent SARS-CoV-2 internalization by interacting with the S-protein/NRP1 complex (27,28).…”

Section: Introductionmentioning

confidence: 99%

Comprehensive analysis and immunohistochemistry localization of NRP1 expression in pancancer and normal individual tissues in relation to SARS‑CoV‑2 susceptibility

Fu,

He,

Zhang

et al. 2023

Exp Ther Med

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Neuropilin 1 (NRP1/CD304) is a typical membrane-bound co-receptor for vascular endothelial growth factor, semaphorin family members and viral severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, NRP1 expression levels across cancer types and the potential role of SARS-CoV-2 infection in patients with cancer are not clear. Online databases, such as The Cancer Genome Atlas database of Human Protein Atlas, Gene Expression Profiling Interactive Analysis and cBioPortal were used for the expression analysis in this study. Immunohistochemical (IHC) staining for NRP1 was performed in the tissues of patients with non-small cell carcinoma. As a result, it was found that NRP1 mRNA and protein expression levels were highest in the female reproductive tissues and the respiratory system, specifically in the nasopharynx, bronchus and fallopian tube, as well as in adipocytes, hepatic stellate cells, Sertoli cells, endothelial cells and dendritic cells. IHC showed that the NRP1 protein was mainly localized to the cytoplasm and membrane in the tissues of patients with non-small cell carcinoma, demonstrating its role in lung infection by SARS-CoV-2, due to invasion of cell membranes by the virus. Levels of NRP1 mRNA were significantly increased in lymphoid neoplasm diffuse large B-cell lymphoma, esophageal carcinoma, glioblastoma multiforme, head and neck squamous cell carcinoma, kidney renal clear cell carcinoma (KIRC), pancreatic adenocarcinoma, stomach adenocarcinoma and thymoma, and significantly decreased in cervical squamous cell carcinoma and endocervical adenocarcinoma, kidney chromophobe, lung squamous cell carcinoma, ovarian serous cystadenocarcinoma, uterine corpus endometrial carcinoma and uterine carcinosarcoma, compared with corresponding healthy tissues in pancancer, indicating roles for viral invasion in most cancer types. Moreover, low NRP1 expression was significantly associated with long overall survival (OS) time in adrenocortical carcinoma, brain lower grade glioma, stomach adenocarcinoma and uveal melanoma, but with short OS time in KIRC only. The ENST00000374867.6 (NRP1-202) isoform is most highly expressed in most cancer types and thus could be involved in tumorigenesis and SARS-CoV-2 invasion in cancer patients. NRP1 may be involved in SARS-CoV-2 invasion in patients with cancer, including those with lung cancer.

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Discovery of natural products to block SARS-CoV-2 S-protein interaction with Neuropilin-1 receptor: A molecular dynamics simulation approach

Cited by 7 publications

References 71 publications

Computational Screening of Neuropilin‐1 Unveils Novel Potential Anti‐SARS‐CoV‐2 Therapeutics

Computational Screening of Neuropilin‐1 Unveils Novel Potential Anti‐SARS‐CoV‐2 Therapeutics

New Crystal Form of Human Neuropilin-1 b1 Fragment with Six Electrostatic Mutations Complexed with KDKPPR Peptide Ligand

Comprehensive analysis and immunohistochemistry localization of NRP1 expression in pancancer and normal individual tissues in relation to SARS‑CoV‑2 susceptibility

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