Discovery of Small-Molecule Inhibitors of SARS-CoV-2 Proteins Using a Computational and Experimental Pipeline (original) (raw)
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Structure-based identification of potential SARS-CoV-2 main protease inhibitors
Journal of Biomolecular Structure and Dynamics, 2020
To address coronavirus disease (COVID-19), currently, no effective drug or vaccine is available. In this regard, molecular modeling approaches are highly useful to discover potential inhibitors of the main protease (M pro) enzyme of SARS-CoV-2. Since, the M pro enzyme plays key roles in mediating viral replication and transcription; therefore, it is considered as an attractive drug target to control SARS-CoV-2 infection. By using structure-based drug design, pharmacophore modeling, and virtual high throughput drug screening combined with docking and all-atom molecular dynamics simulation approach, we have identified five potential inhibitors of SARS-CoV-2 M pro. MD simulation studies revealed that compound 54035018 binds to the M pro with high affinity (DG bind À37.40 kcal/mol), and the complex is more stable in comparison with other protein-ligand complexes. We have identified promising leads to fight COVID-19 infection as these compounds fulfill all drug-likeness properties. However, experimental and clinical validations are required for COVID-19 therapy.
Frontiers in Chemistry
SARS-CoV-2 triggered a worldwide medical crisis, affecting the world’s social, emotional, physical, and economic equilibrium. However, treatment choices and targets for finding a solution to COVID-19’s threat are becoming limited. A viable approach to combating the threat of COVID-19 is by unraveling newer pharmacological and therapeutic targets pertinent in the viral survival and adaptive mechanisms within the host biological milieu which in turn provides the opportunity to discover promising inhibitors against COVID-19. Therefore, using high-throughput virtual screening, manually curated compounds library from some medicinal plants were screened against four main drivers of SARS-CoV-2 (spike glycoprotein, PLpro, 3CLpro, and RdRp). In addition, molecular docking, Prime MM/GBSA (molecular mechanics/generalized Born surface area) analysis, molecular dynamics (MD) simulation, and drug-likeness screening were performed to identify potential phytodrugs candidates for COVID-19 treatment....
Journal of Molecular Modeling
A novel coronavirus known as severe acute respiratory syndrome is rapidly spreading worldwide. The international health authorities are putting all their efforts on quick diagnosis and placing the patients in quarantine. Although different vaccines have come for quick use as prophylactics, drug repurposing seems to be of paramount importance because of inefficient therapeutic options and clinical trial limitations. Here, we used structure-based drug designing approach to find and check the efficacy of the possible drug that can inhibit coronavirus main protease which is involved in polypeptide processing to functional protein. We performed virtual screening, molecular docking and molecular dynamics simulations of the FDAapproved drugs against the main protease of SARS-CoV-2. Using well-defined computational methods, we identified amprenavir, cefoperazone, riboflavin, diosmin, nadide and troxerutin approved for human therapeutic uses, as COVID-19 main protease inhibitors. These drugs bind to the SARS-CoV-2 main protease conserved residues of substrate-binding pocket and formed a remarkable number of non-covalent interactions. We have found diosmin as an inhibitor which binds covalently to the COVID-19 main protease. This study provides enough evidences for therapeutic use of these drugs in controlling COVID-19 after experimental validation and clinical demonstration.
Severe acute respiratory syndrome coronavirus (SARS-CoV-2) is an emerging new viral pathogen that causes severe respiratory disease. SARS-CoV-2 is responsible for an outbreak of COVID-19 pandemic worldwide. As there are no confirmed antiviral drugs or vaccines currently available for the treatment of COVID-19, discovering potent inhibitors or vaccines are urgently required for the benefit of humanity. The glycosylated Spike protein (S-protein) directly interacts with human angiotensin-converting enzyme 2 (ACE2) receptor through the receptor-binding domain (RBD) of S-protein. As the S-protein is exposed to the surface and is essential for entry into the host, the S-protein can be considered as a first-line therapeutic target for antiviral therapy and vaccine development. In-silico screening, docking and molecular dynamics simulation studies were performed to identify repurposing drugs using DrugBank and PubChem library against the RBD of S-protein. The study identified a laxative dru...
journal of applied pharmaceutical science, 2022
A threat to the global human population has been established by the COVID-19 pandemic in 2020 and it is quite challenging to identify innovative medications in this epidemic. These are zoonotic and can potentially create massive outbreaks of illnesses that can result in morbidity and death. As a consequence, natural therapies for the anticipation and dealing of COVID-19 are widely acknowledged as a quick means to find successful therapeutic choices that can be found through in-silico drug screening tests. RNA-dependent RNA polymerase (RdRp), a vital precursor involved in the virus's life cycle, is present in SARS-CoV-2. Blocking the formation of the RdRp-RNA complex inhibits viral replica and boosts the immune response of the host. In our present research, with the use of a SuperNatural Database, we started the high-throughput virtual screening method to recognize inhibitors aiming for SARS-CoV-2 RdRp. According to extra-precision docking data, two compounds, SN00293542 and SN00391842 had −14.79 and −14.65 kcal/mol docking scores, respectively. In addition, Prime molecular mechanics generalized bond surface area research has identified hydrophobic energy and Van der Waal energy footings as significant contributions towards total binding free energy. Additionally, a hundred nanosecond Molecular dynamics simulation of the SN00391842/7D4F complex was run to determine its dynamic behavior.
Journal of Biomolecular Structure and Dynamics, 2020
SARS-CoV-2 is liable for the worldwide coronavirus disease (COVID-19) exigency. This pandemic created the need for all viable treatment strategies available in the market. In this scenario, computeraided drug design techniques can be efficiently applied for the quick identification of promising drug repurposing candidates. In the current study, we applied the molecular docking approach in conjugation with molecular dynamics (MD) simulations to find out potential inhibitors against M pro of SARS-CoV-2 from previously reported SARS-3CL protease inhibitors. Our results showed that N-substituted isatin derivatives and pyrazolone compounds could be used as a potent inhibitor and may possess an anti-viral activity against SARS-CoV-2. However, further experimental investigation and validation of the selected hits are required to find out their suitability for clinical trials.
Journal of Biomolecular Structure and Dynamics, 2020
Recent outbreak of novel coronavirus and its rapid pandemic escalation in all over the world has drawn the attention to urgent need for effective drug development. However, due to prolonged vaccine and drug development procedure against a newly emerged devastating SARS-CoV-2 virus pathogen, repurposing of existing potential pertinent drug molecules would be preferable strategy to reduce mortality immediately and further development of new drugs to combat overall global Covid19 crisis in all over the world. Herein, we have filtered 23 prospective drug candidates through literature review. Assessing evidences from molecular docking studies, it was clearly seen that, Epirubicin, Vapreotida, and Saquinavir exhibited better binding affinity against SARS-CoV-2 Main Protease than other drug molecules among the 23 potential inhibitors. However, 50 ns molecular dynamics simulation indicated the less mobile nature of the docked complex maintaining structural integrity. Our overall prediction findings indicate that Epirubicin, Vapreotida, and Saquinavir may inhibit COVID-19 by synergistic interactions in the active cavity and those results can pave the way in drug discovery although it has to be further validated by in-vitro and in-vivo investigations.
2020
BackgroundThe current Novel Coronavirus (SARS-CoV-2) pandemic is the third major outbreak of the 21st century which emerged in December 2019 from Wuhan, China. At present there are no known treatments or vaccines to cure or prevent the illness.ObjectiveThe objective of this study was to explore a list of potential drugs (herbal and antivirals) for their role in inhibiting activity and or replication of SARS-CoV-2 by using molecular docking onto the crystal structures of key viral proteins.MethodologyIn this study, we used molecular docking to estimate the binding affinities of 3699 drugs on the potential active sites of the 6 main SARS-CoV-2 proteins (Papain like protease, Main protease, ADP Ribose phosphatase, Spike protein, NSP-9 and NSP-10 to 16 complex). While other studies have mostly been performed on the homology models, we obtained the most recently submitted crystal structures of all 6 proteins from the protein data bank for this analysis.ResultsOur results showed the top l...
Applied Microbiology: Theory ＆ Technology, 2021
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-COV-2) is a causative agent of the potentially fatal coronavirus disease (COVID-19). Coronavirus targets the human respiratory system primarily. It can also infect the gastrointestinal, hepatic, and central nervous systems of humans, avians, bats, livestock, mice, and many other wild animals, as these are primary targets of the pathogen. This study aims to screen out the most potent inhibitor for SARS-CoV-2 (COVID-19) spike glycoproteins among the selected drugs, and computational tools have been utilized for this purpose. The selected drugs have been designed to explore their structural properties in this study by molecular orbital calculation. To inhibit the spike glycoproteins, the performance of these drugs was also examined by molecular docking calculation. In improving the performance of drugs, non-bond interactions play a significant role. To determine the chemical reactivity of all the medicines, HOMO and LUMO energy values were also calculated. The combined calculations exhibited that Ledipasvir among the selected drugs can be the most potent drug to treat SARS-CoV-2 compared to other medications.
Molecular Diversity
Worldwide coronavirus disease 2019 (COVID-19) outbreak is still threatening global health since its outbreak first reported in the late 2019. The causative novel virus has been designated as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although COVID-19 emergent with significant mortality, there is no availability of definite treatment measures. It is now extremely desirable to identify potential chemical entities against SARS-CoV-2 for the treatment of COVID-19. In the present study, a state-of-art virtual screening protocol was implemented on three anti-viral specific chemical libraries against SARS-CoV-2 main protease (Mpro). Particularly, viewing the large-scale biological role of Mpro in the viral replication process it has been considered as a prospective anti-viral drug target. Herein, on collected 79,892 compounds, hierarchical multistep docking followed by relative binding free energy estimation has been performed. Thereafter, implying a user-defined XP-doc...