key: cord-0831792-pimtk320 authors: Humayun, Fahad; Khan, Abbas; Ahmad, Sajjad; Yuchen, Wang; Wei, Guoshen; Nizam-Uddin, N.; Hussain, Zahid; Khan, Wajid; Zaman, Nasib; Rizwan, Muhammad; Waseem, Muhammad; Wei, Dong-Qing title: Abrogation of SARS-CoV-2 interaction with host (NRP1) Neuropilin-1 receptor through high-affinity marine natural compounds to curtail the infectivity: A structural-dynamics data date: 2021-07-31 journal: Comput Biol Med DOI: 10.1016/j.compbiomed.2021.104714 sha: 65c2af1934d671e47e8169e81c8a8f28461318fc doc_id: 831792 cord_uid: pimtk320 The evolution of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants around the globe has made the coronavirus disease 2019 (COVID-19) pandemic more worrisome, pressuring the health care system and resulting in an increased mortality rate. Recent studies recognized neuropilin-1 (NRP1) as a key facilitator in the invasion of the new SARS-CoV-2 into the host cell. Therefore, it is considered an imperative drug target for the treatment of COVID-19. Hence, a thorough analysis was needed to understand the impact and to guide new therapeutics development. In this study, we used structural and biomolecular simulation techniques to identify novel marine natural products which could block this receptor and stop the virus entry. We discovered that the binding affinity of CMNPD10175, CMNPD10017, CMNPD10114, CMNPD10115, CMNPD10020. CMNPD10018, CMNPD10153, CMNPD10149 CMNPD10464 and CMNPD10019 were substantial during the virtual screening (VS). We further explored these compounds by analyzing their absorption, distribution, metabolism, and excretion and toxicity (ADMET) properties and structural-dynamics features. Free energy calculations further established that all the compounds exhibit strong binding energy for NRP1. Consequently, we hypothesized that these compounds might be the best lead candidates for therapeutic interventions hindering virus binding to the host cell. This study provides a strong impetus to develop novel drugs against the SARS-CoV-2 by targeting NRP1. The global coronavirus disease 2019 (COVID-19) pandemic was caused by acute respiratory 63 syndrome coronavirus 2 (SARS-CoV-2), a highly contagious virus first identified in Wuhan, 64 China [1] . In 2013, a similar coronavirus named SARS-CoV caused an epidemic. SARS-CoV-2 65 infects the lower respiratory system and spreads quickly, mainly via pharyngeal viral shedding 66 [2, 3] . Angiotensin-converting enzyme 2 (ACE2), a host receptor, is responsible for the uptake of can enable the receptor-mediated endocytosis of the virus. NRP1 is also recognized as a cellular 75 signalling and cell surface receptor [7, 8] . The host receptor binding protein of SARS-CoV-2, 76 known as the spike protein, is cleaved into S1 and S2 polypeptides by protease and furin within 77 the host cell, thus exposing the CendR motif in the cleaved S1 protein. The CendR motif is 78 named after the C-end terminal rule requiring the presence of a cationic amino acid, generally 79 arginine, at the carboxyl terminus, which causes an RXXR configuration in the ligand. The The conclusions of these well-designed studies indicate that NRP1 may act as a host cell 96 mediator to enhance the virus's attachment and entry into host cells; thus, it may maximize tissue 97 tropism of SARS-CoV-2 [15] . Therefore, in the present study, molecular modelling-based 98 approaches were employed to target NRP1 in order to identify novel hits against SARS-CoV-2 99 within a comprehensive marine natural products (CMNP) database (https://www.cmnpd.org/). Computational structural biology and biophysical approaches are the most widely used 101 J o u r n a l P r e -p r o o f approaches in drug discovery for the treatment of viral pathogens [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] . We used virtual drug 102 screening approaches and binding free energy calculations to decipher the binding, possible 103 mechanism, and long-term association strength between the identified drugs and NRP1. These 104 efforts to discover effective drug candidates for the treatment of COVID-19 will help combat the 105 infection caused by SARS-CoV-2. Here, ΔGbind denotes total free binding energy, while others denote the free energy of the protein, score and interactions with the key residues, ten compounds were shortlisted for further analysis. The identified top ten compounds are given in Table 2 . These compounds were further analyzed such as GPCR, Ion Channels, Kinases, protease and enzymes are also given in for CMNPD10020, the prodigy score was predicted to be -7.1 kcal/mol. This shows the tighter 304 binding of these molecules with the host receptor NRP1 and its inhibition. The predicted scores 305 by prodigy are given in Table 3 . In conclusion, this study identified novel hits from the marine sources against SARS-CoV-2 402 NRP1 receptor. Though the findings of the current work are promising, the study suffers from The 2019-new 439 coronavirus epidemic: Evidence for virus evolution Clinical 441 characteristics of 2019 novel coronavirus infection in China, MedRxiv Clinical features of 443 patients infected with 2019 novel coronavirus in Wuhan, China, The lancet Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation Deep mutational scanning of SARS-CoV-2 receptor binding domain reveals 449 constraints on folding and ACE2 binding Not only ACE2-the quest for additional host cell 451 mediators of SARS-CoV-2 infection: Neuropilin-1 (NRP1) as a novel SARS-CoV-2 host cell entry mediator 452 implicated in COVID-19 Neuropilin-1 is a host factor for SARS-CoV-2 infection Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity The role of Neuropilin-1 in 460 COVID-19 SARS-CoV-2 Spike protein co-opts VEGF-A/Neuropilin-1 receptor signaling to induce analgesia, 463 Pain Neuropilin-1 facilitates SARS-CoV-2 cell entry and provides a possible pathway into 466 the central nervous system The structural basis of accelerated host cell entry by SARS-CoV-2, The FEBS 469 journal C-end rule peptides mediate neuropilin-1-471 dependent cell, vascular, and tissue penetration Neuropilin functions as an essential cell surface receptor New insights into the physiopathology of COVID-19: SARS-CoV-476 2-associated gastrointestinal illness Immunoinformatic 478 Analysis of T-and B-Cell Epitopes for SARS-CoV-2 Vaccine Design, Vaccines Immunoinformatics characterization of SARS-CoV-2 spike 480 glycoprotein for prioritization of epitope based multivalent peptide vaccine 483 Development of epitope-based peptide vaccine against novel coronavirus 2019 (SARS-COV-2): 484 Immunoinformatics approach Immunodominant regions prediction of nucleocapsid protein for SARS-CoV-2 early diagnosis: a 487 bioinformatics and immunoinformatics study Designing a next generation multi-epitope based peptide vaccine 489 candidate against SARS-CoV-2 using computational approaches 491 Combined drug repurposing and virtual screening strategies with molecular dynamics simulation 492 identified potent inhibitors for SARS-CoV-2 main protease (3CLpro) Higher 495 infectivity of the SARS-CoV-2 new variants is associated with K417N/T, E484K, and N501Y mutants: An 496 insight from structural data In silico 498 and in vitro evaluation of kaempferol as a potential inhibitor of the SARS-CoV-2 main protease (3CLpro) 501 Phylogenetic analysis and structural perspectives of RNA-dependent RNA SARs-CoV-2 with natural products Preliminary Structural Data Revealed that the SARS-CoV-2 B. 1.617 Variant's RBD binds to 505 ACE2 receptor stronger than the Wild Type to Enhance the Infectivity FAF-Drugs4: free ADME-tox filtering 507 computations for chemical biology and early stages drug discovery The RCSB protein data bank: integrative view of protein, gene and 3D structural 511 information UCSF 513 Chimera-a visualization system for exploratory research and analysis Software extensions to UCSF chimera for interactive 516 visualization of large molecular assemblies Small-molecule library screening by docking with PyRx, Chemical biology AutoDock Vina: improving the speed and accuracy of docking with a new 520 scoring function, efficient optimization, and multithreading CMNPD: a comprehensive marine natural 523 products database towards facilitating drug discovery from the ocean AutoDockFR: Advances in Protein-526 Ligand Docking with Explicitly Specified Binding Site Flexibility SwissADME: a free web tool to evaluate pharmacokinetics, drug-529 likeness and medicinal chemistry friendliness of small molecules PRODIGY: a web server for 531 predicting the binding affinity of protein-protein complexes The Amber biomolecular simulation programs A modified TIP3P water potential for simulation with Ewald summation CPPTRAJ: software for processing and analysis of molecular 538 dynamics trajectory data Assessing the performance of MM/PBSA and MM/GBSA methods. 540 4. Accuracies of MM/PBSA and MM/GBSA methodologies evaluated by various simulation protocols 541 using PDBbind data set Characterization of domain-peptide interaction interface: prediction of 543 SH3 domain-mediated protein-protein interaction network in yeast by generic structure-based models Assessing the performance of the MM/PBSA and 546 MM/GBSA methods. 6. Capability to predict protein-protein binding free energies and re-rank binding 547 poses generated by protein-protein docking MMPBSA py: an 550 efficient program for end-state free energy calculations The systematic modeling 553 studies and free energy calculations of the phenazine compounds as anti-tuberculosis agents Deep-learning-based target screening and 556 similarity search for the predicted inhibitors of the pathways in Parkinson's disease, RSC advances Functional assessment of cell entry and receptor usage for SARS-559 CoV-2 and other lineage B betacoronaviruses Structure of the 561 SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor Virtual screening for the discovery of active principles from natural 563 products, Natural products as source of molecules with therapeutic potential Journal of Natural 567 Products Synthesis and biological activities of isogranulatimide analogues Luisols A and B, new aromatic tetraols produced by an estuarine 572 marine bacterium of the genus Streptomyces (Actinomycetales) Flavonoids 575 from Marine-Derived Actinobacteria as Anticancer Drugs Meridianins: Marine-derived potent kinase 577 inhibitors, Mini reviews in medicinal chemistry Small molecule inhibitors of the neuropilin-1 vascular endothelial growth factor A (VEGF-A) 580 interaction Small molecule neuropilin-1 antagonists combine antiangiogenic and antitumor 583 activity with immune modulation through reduction of transforming growth factor beta (TGFβ) 584 production in regulatory T-cells Discovery of novel inhibitors of 586 vascular endothelial growth factor-A-Neuropilin-1 interaction by structure-based virtual screening Simultaneous measurement of 10,000 protein-ligand affinity constants 590 using microarray-based kinetic constant assays, Assay and drug development technologies High throughput, label-free screening small molecule compound libraries 593 for protein-ligands using combination of small molecule microarrays and a special ellipsometry-based 594 optical scanner Protein reactions with surface-bound molecular targets detected by 596 oblique-incidence reflectivity difference microscopes The computational resources were provided by the Pengcheng Lab. HPC