Denovo designing, retrosynthetic analysis, and combinatorial synthesis of a hybrid antiviral (VTAR-01) to inhibit the interaction of SARS-CoV2 spike glycoprotein with human angiotensin-converting enzyme 2

Tiwari, Vishvanath

doi:10.1242/bio.054056

Cited by 10 publications

(12 citation statements)

References 51 publications

(62 reference statements)

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“…8 ). In silico screening, molecular mechanics, and molecular dynamics simulation (MDS) research indicate that at the receptor-binding domain that recognizes hACE-2 (RBD–hACE2) interface, ribavirin has strong interaction (Tiwari et al 2020 ). It has the binding affinity (− 6.8 kcal/mol) and formed 5 hydrogen bonds (Trp617, Asp761, Lys798, His810 and Glu811) and 3 hydrophobic contacts (Trp800, Phe812, Cys813) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Screening of potent drug inhibitors against SARS-CoV-2 RNA polymerase: an in silico approach

2021

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has emerged as a rapidly escalating serious global health issue, affecting every section of population in a detrimental way. Present situation invigorated researchers to look for potent targets, development as well as repurposing of conventional therapeutic drugs. NSP12, a RNA polymerase, is key player in viral RNA replication and, hence, viral multiplication. In our study, we have screened a battery of FDA-approved drugs against SARS-CoV-2 RNA polymerase using in silico molecular docking approach. Identification of potent inhibitors against SARS-CoV-2 NSP12 (RNA polymerase) were screeened from FDA approved drugs by virtual screening for therapeutic applications in treatment of COVID-19. In this study, virtual screening of 1749 antiviral drugs was executed using AutoDock Vina in PyRx software. Binding affinities between NSP12 and drug molecules were determined using Ligplot + and PyMOL was used for visualization of docking between interacting residues. Screening of 1749 compounds resulted in 14 compounds that rendered high binding affinity for NSP12 target molecule. Out of 14 compounds, 5 compounds which include 3a (Paritaprevir), 3d (Glecaprevir), 3h (Velpatasvir), 3j (Remdesivir) and 3l (Ribavirin) had a binding affinity of − 10.2 kcal/mol, −9.6 kcal/mol, − 8.5 kcal/mol, − 8.0 kcal/mol and − 6.8 kcal/mol, respectively. Moreover, a number of hydrophobic interactions and hydrogen bonding between these 5 compounds and NSP12 active site were observed. Further, 3l (Ribavirin) was docked with 6M71 and molecular dynamic simulation of the complex was also performed to check the stability of the conformation. In silico analysis postulated the potential of conventional antiviral drugs in treatment of COVID-19. However, these finding may be further supported by experimental data for its possible clinical application in present scenario.

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Section: Resultsmentioning

confidence: 99%

Screening of potent drug inhibitors against SARS-CoV-2 RNA polymerase: an in silico approach

2021

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“…baumannii (Tiwari, Tiwari, et al, 2018). Recently, there have been different novel approaches such as hybrid designed lead (Tiwari et al, 2021; Tiwari, 2020a), denovo designed lead (Tiwari, 2020a; Tiwari, 2021), pharmacophore‐based designed lead (Tiwari, Panwar, et al, 2020) against the different pathogens. Curcumin‐thalidomide hybrids show high predicted binding to RecA compared to the curcumin analogs for E .…”

Section: Discussionmentioning

confidence: 99%

Pharmacophore screening, denovo designing, retrosynthetic analysis, and combinatorial synthesis of a novel lead VTRA1.1 against RecA protein of Acinetobacter baumannii

Tiwari

2022

Chem Biol Drug Des

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Antibiotics and disinfectants resistance is acquired by activating RecA-mediated DNA repair, which maintains ROS-dependent DNA damage caused by the antimicrobial molecules. To increase the efficacy of different antimicrobials, an inhibitor can be developed against RecA protein. The present study aims to design a denovo inhibitor against RecA protein of Acinetobacter baumannii.Pharmacophore-based screening, molecular mechanics, molecular dynamics simulation (MDS), retrosynthetic analysis, and combinatorial synthesis were used to design lead VTRA1.1 against RecA of A. baumannii. Pharmacophore models (structure-based and ligand-based) were created, and a phase library of FDA-approved drugs was prepared. Screening of the phase library against these pharmacophore models selected thirteen lead molecules. These filtered leads were used for the denovo fragment-based design, which produced 253 combinations. These designed molecules were further analyzed for its interaction with active site of RecA that selected a hybrid VTRA1. Further, retrosynthetic analysis and combinatorial synthesis produced 1000 analogs of VTRA1 by more than 100 modifications. These analogs were used for XP docking, binding free energy calculation, and MDS analysis which finally select lead VTRA1.1 against RecA protein. Further, mutations at the interacting residues of RecA with VTRA1.1, alter the unfolding rate of RecA, which suggests the binding of VTRA1.1 to these residues may alter the stability of RecA. It is also found that VTRA1.1 had reduced interaction of RecA with LexA and ssDNA polydT, showing the lead's efficacy in controlling the SOS response. Further, it was also observed that VTRA1.1 does not contain any predicted human off-targets and no cytotoxicity to cell lines.As functional RecA is involved in antimicrobial resistance, denovo designed lead VTRA1.1 against RecA may be further developed as a significant combination for therapeutic uses against A. baumannii.

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“…In the present study, a multiepitope vaccine constructs VTC3 for SARS CoV2 have been proposed with the help of reverse vaccinology that compiles the outer surface-exposed epitopes of the structural and non-structural proteins of this virus. There are different therapeutic strategies, and ongoing research has been tried to control SARS CoV2 ( Felsenstein et al, 2020 ; Tiwari, 2020b , 2020a ). Although different groups have tried to design a vaccine against SARS-CoV2, the present study reports a comprehensive approach to design a vaccine construct that taking care of all possible design shortcomings such as absence of surface epitopes, inappropriate TLRs interactions, less population coverage, interaction with the human microbiome, presence of cross-reactivity with human proteins, epitope form mutation hot spots and absence of immune response, etc.…”

Section: Discussionmentioning

confidence: 99%

Immunoinformatic approach to design a multiepitope vaccine targeting non-mutational hotspot regions of structural and non-structural proteins of the SARS CoV2

Solanki¹,

Tiwari²,

Tiwari³

2021

PeerJ

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Background The rapid Severe Acute Respiratory Syndrome Coronavirus 2 (SARS CoV2) outbreak caused severe pandemic infection worldwide. The high mortality and morbidity rate of SARS CoV2 is due to the unavailability of vaccination and mutation in this virus. The present article aims to design a potential vaccine construct VTC3 targeting the non-mutational region of structural and non-structural proteins of SARS CoV2. Methods In this study, vaccines were designed using subtractive proteomics and reverse vaccinology. To target the virus adhesion and evasion, 10 different structural and non-structural proteins have been selected. Shortlisted proteins have been screened for B cell, T cell and IFN gamma interacting epitopes. 3D structure of vaccine construct was modeled and evaluated for its physicochemical properties, immunogenicity, allergenicity, toxicity and antigenicity. The finalized construct was implemented for docking and molecular dynamics simulation (MDS) with different toll-like receptors (TLRs) and human leukocyte antigen (HLA). The binding energy and dissociation construct of the vaccine with HLA and TLR was also calculated. Mutational sensitivity profiling of the designed vaccine was performed, and mutations were reconfirmed from the experimental database. Antibody production, clonal selection, antigen processing, immune response and memory generation in host cells after injection of the vaccine was also monitored using immune simulation. Results Subtractive proteomics identified seven (structural and non-structural) proteins of this virus that have a role in cell adhesion and infection. The different epitopes were predicted, and only extracellular epitopes were selected that do not have similarity and cross-reactivity with the host cell. Finalized epitopes of all proteins with minimum allergenicity and toxicity were joined using linkers to designed different vaccine constructs. Docking different constructs with different TLRs and HLA demonstrated a stable and reliable binding affinity of VTC3 with the TLRs and HLAs. MDS analysis further confirms the interaction of VTC3 with HLA and TLR1/2 complex. The VTC3 has a favorable binding affinity and dissociation constant with HLA and TLR. The VTC3 does not have similarities with the human microbiome, and most of the interacting residues of VTC3 do not have mutations. The immune simulation result showed that VTC3 induces a strong immune response. The present study designs a multiepitope vaccine targeting the non-mutational region of structural and non-structural proteins of the SARS CoV2 using an immunoinformatic approach, which needs to be experimentally validated.

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Denovo designing, retrosynthetic analysis, and combinatorial synthesis of a hybrid antiviral (VTAR-01) to inhibit the interaction of SARS-CoV2 spike glycoprotein with human angiotensin-converting enzyme 2

Cited by 10 publications

References 51 publications

Screening of potent drug inhibitors against SARS-CoV-2 RNA polymerase: an in silico approach

Screening of potent drug inhibitors against SARS-CoV-2 RNA polymerase: an in silico approach

Pharmacophore screening, denovo designing, retrosynthetic analysis, and combinatorial synthesis of a novel lead VTRA1.1 against RecA protein of Acinetobacter baumannii

Immunoinformatic approach to design a multiepitope vaccine targeting non-mutational hotspot regions of structural and non-structural proteins of the SARS CoV2

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