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Mutational analysis in international isolates and drug repurposing against SARS-CoV-2 spike protein: molecular docking and simulation approach.

ABSTRACT: The novel SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) is spreading, as the causative pathogen of coronavirus disease-19 (COVID-19). It has infected more than 1.65 billion people all over the world since it was discovered and reported 3.43 million deaths by mid of May 2021. SARS-CoV-2 enters the host cell by binding to viral surface glycoprotein (S protein) with human ACE2 (angiotensin-converting enzyme2). Spike protein (contains S1 and S2 sub-domains) molecular interaction with the host cells is considered as a major step in the viral entry and disease initiation and progression and this identifies spike protein as a promising therapeutic target against antiviral drugs. Currently, there are no efficient antiviral drugs for the prevention of COVID-19 infection. In this study, we have analyzed global 8719 spike protein sequences from patients infected with SAR-CoV-2. These SAR-CoV-2 genome sequences were downloaded from the GISAID database. By using an open reading frame (ORF) tool we have identified the spike protein sequence. With these, all spike protein amino acid sequences are subjected to multiple sequence alignment (MSA) with Wuhan strain spike protein sequence as a query sequence, and it shows all SAR-CoV strain spike proteins are 99.8% identical. In the mutational analysis, we found 639 mutations in the spike protein sequence of SARS-CoV-2 and identified/highlighted 20 common mutations L5F, T22I, T29I, H49Y, L54F, V90F, S98F, S221L, S254F, V367F, A520S, T572I, D614G, H655Y, P809S, A879S, D936Y, A1020S, A1078S, and H1101Y. Further, we have analyzed the crystal structure of the 2019-nCoV chimeric receptor-binding complex with ACE2 (PDB ID: 6VW1) as a major target protein. The spike receptor binding protein (RBD) used as target region for our studies with FDA-approved drugs for repurposing, and identified few anti-SARS-CoV2 potential drugs (Silmitasertib, AC-55541, Merimepodib, XL413, AZ3451) based on their docking score and binding mode calculations expected to strongly bind to motifs of ACE2 receptor and may show impart relief in COVID-19 patients.

SUBMITTER: Pulakuntla S

PROVIDER: S-EPMC8282177 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:For the last two years, the COVID-19 pandemic has continued to bring consternation on most of the world. According to recent WHO estimates, there have been more than 5.6 million deaths worldwide. The virus continues to evolve all over the world, thus requiring both vigilance and the necessity to find and develop a variety of therapeutic treatments, including the identification of specific antiviral drugs. Multiple studies have confirmed that SARS-CoV-2 utilizes its membrane-bound spike protein to recognize human angiotensin-converting enzyme 2 (ACE2). Thus, preventing spike-ACE2 interactions is a potentially viable strategy for COVID-19 treatment as it would block the virus from binding and entering into a host cell. This work aims to identify potential drugs using an in silico approach. Molecular docking was carried out on both approved drugs and substances previously tested in vivo. This step was followed by a more detailed analysis of selected ligands by molecular dynamics simulations to identify the best molecules that thwart the ability of the virus to interact with the ACE2 receptor. Because the SARS-CoV-2 virus evolves rapidly due to a plethora of immunocompromised hosts, the compounds were tested against five different known lineages. As a result, we could identify substances that work well on individual lineages and those showing broader efficacy. The most promising candidates among the currently used drugs were zafirlukast and simeprevir with an average binding affinity of -22 kcal/mol for spike proteins originating from various lineages. The first compound is a leukotriene receptor antagonist that is used to treat asthma, while the latter is a protease inhibitor used for hepatitis C treatment. From among the in vivo tested substances that concurrently exhibit promising free energy of binding and ADME parameters (indicating a possible oral administration) we selected the compound BDBM50136234. In conclusion, these molecules are worth exploring further by in vitro and in vivo studies against SARS-CoV-2.

Project description:Severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2 is a virus that belongs to the Coronaviridae family. This group of viruses commonly causes colds but possesses a tremendous pathogenic potential. In humans, an outbreak of SARS caused by the SARS-CoV virus was first reported in 2003, followed by 2012 when the Middle East respiratory syndrome coronavirus (MERS-CoV) led to an outbreak of Middle East respiratory syndrome (MERS). Moreover, COVID-19 represents a serious socioeconomic and global health problem that has already claimed more than four million lives. To date, there are only a handful of therapeutic options to combat this disease, and only a single direct-acting antiviral, the conditionally approved remdesivir. Since there is an urgent need for active drugs against SARS-CoV-2, the strategy of drug repurposing represents one of the fastest ways to achieve this goal. An in silico drug repurposing study using two methods was conducted. A structure-based virtual screening of the FDA-approved drug database on SARS-CoV-2 main protease was performed, and the 11 highest-scoring compounds with known 3CLpro activity were identified while the methodology was used to report further 11 potential and completely novel 3CLpro inhibitors. Then, inverse molecular docking was performed on the entire viral protein database as well as on the Coronaviridae family protein subset to examine the hit compounds in detail. Instead of target fishing, inverse docking fingerprints were generated for each hit compound as well as for the five most frequently reported and direct-acting repurposed drugs that served as controls. In this way, the target-hitting space was examined and compared and we can support the further biological evaluation of all 11 newly reported hits on SARS-CoV-2 3CLpro as well as recommend further in-depth studies on antihelminthic class member compounds. The authors acknowledge the general usefulness of this approach for a full-fledged inverse docking fingerprint screening in the future.

Project description:Introduction: The perpetual appearance of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-COV-2), and its new variants devastated the public health and social fabric around the world. Understanding the genomic patterns and connecting them to phenotypic attributes is of great interest to devise a treatment strategy to control this pandemic. Materials and Methods: In this regard, computational methods to understand the evolution, dynamics and mutational spectrum of SARS-CoV-2 and its new variants are significantly important. Thus, herein, we used computational methods to screen the genomes of SARS-CoV-2 isolated from Pakistan and connect them to the phenotypic attributes of spike protein; we used stability-function correlation methods, protein-protein docking, and molecular dynamics simulation. Results: Using the Global initiative on sharing all influenza data (GISAID) a total of 21 unique mutations were identified, among which five were reported as stabilizing while 16 were destabilizing revealed through mCSM, DynaMut 2.0, and I-Mutant servers. Protein-protein docking with Angiotensin-converting enzyme 2 (ACE2) and monoclonal antibody (4A8) revealed that mutation G446V in the receptor-binding domain; R102S and G181V in the N-terminal domain (NTD) significantly affected the binding and thus increased the infectivity. The interaction pattern also revealed significant variations in the hydrogen bonding, salt bridges and non-bonded contact networks. The structural-dynamic features of these mutations revealed the global dynamic trend and the finding energy calculation further established that the G446V mutation increases the binding affinity towards ACE2 while R102S and G181V help in evading the host immune response. The other mutations reported supplement these processes indirectly. The binding free energy results revealed that wild type-RBD has a TBE of -60.55 kcal/mol while G446V-RBD reported a TBE of -73.49 kcal/mol. On the other hand, wild type-NTD reported -67.77 kcal/mol of TBE, R102S-NTD reported -51.25 kcal/mol of TBE while G181V-NTD reported a TBE of -63.68 kcal/mol. Conclusions: In conclusion, the current findings revealed basis for higher infectivity and immune evasion associated with the aforementioned mutations and structure-based drug discovery against such variants.

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Mutational analysis in international isolates and drug repurposing against SARS-CoV-2 spike protein: molecular docking and simulation approach.

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