Possible SARS-coronavirus 2 inhibitor revealed by simulated molecular docking to viral main protease and host toll-like receptor

Aim: SARS-coronavirus 2 main protease (Mpro) and host toll-like receptors (TLRs) were targeted to screen potential inhibitors among traditional antiviral medicinal plants. Materials & methods: LeDock software was adopted to determine the binding energy between candidate molecules and selected protein pockets. Enrichment analyses were applied to illustrate potential pharmacology networks of active molecules. Results: The citrus flavonoid rutin was identified to fit snugly into the Mpro substrate-binding pocket and to present a strong interaction with TLRs TLR2, TLR6 and TLR7. One-carbon metabolic process and nitrogen metabolism ranked high as potential targets toward rutin. Conclusion: Rutin may influence viral functional protein assembly and host inflammatory suppression. Its affinity for Mpro and TLRs render rutin a potential novel therapeutic anti-coronavirus strategy.

Download Full-text

Gymnema Sylvestre A- Potential Inhibitor of COVID-19 Main Protease by MD Simulation Study

10.26434/chemrxiv.12333251.v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

Senthil Kumar Subramani ◽

Yash Gupta ◽

Manish Manish ◽

GBKS Prasad

Keyword(s):

Md Simulation ◽

Docking Study ◽

Binding Pocket ◽

Gymnema Sylvestre ◽

Molecular Docking Study ◽

Main Protease ◽

Strong Candidate ◽

The Stability ◽

Potential Inhibitors ◽

Domain I

Gymnema sylvestre (GS) is one of the herbal plant used since in ancient times. The present study aimed to assess bioactive compounds GS mainly gymnemic acids as potential inhibitors for COVID-19 against Mpro enzyme using a molecular docking study. The docking score observed between -53.4 to - 42.4 of all gymnemic acids and its derivatives. Molecular Dynamics (MD) simulation studies carried out at 100ns supported the stability of GS molecules within the binding pocket. RMSD score of less than 3.6. mainly, our results supported that these GS molecules bind to the domain I & II, and domain II-III linker of 3CLpro enzyme, suggesting its suitability as strong candidate for therapeutic against COVID-19. <br>

Download Full-text

High-throughput Screening and Experimental Identification of Potent Drugs Targeting SARS-CoV-2 Main Protease

10.21203/rs.3.rs-40014/v1 ◽

2020 ◽

Author(s):

Yan Li ◽

Jinyong Zhang ◽

Ning Wang ◽

Yanjing Zhang ◽

Yongjun Yang ◽

...

Keyword(s):

High Throughput ◽

High Throughput Screening ◽

Drug Targets ◽

Binding Pocket ◽

Substrate Binding Pocket ◽

Stable Conformation ◽

Cross Docking ◽

Main Protease ◽

Computer Based ◽

Old Drugs

Abstract The main protease (Mpro) is one of the best-characterized drug targets among coronaviruses. In the current study, we adopted a multiple cross-docking strategy against different crystal structures of SARS-CoV-2 Mpro to perform computer-based high-throughput virtual screening of possible inhibitors from a drug database using Autodock Vina and SeeSAR software, combined with our in-house automatic processing scripts. The KDs between screened candidates and Mpro were determined using Biacore. Seven drugs were found to fit the substrate-binding pocket of Mpro with a stable conformation, showing high KDs that ranged from 6.79E-7 M to 5.20E-5 M. Finally, mutagenesis studies confirmed that these drugs interact with Mpro specifically, suggesting that our method was reliable and convincing. Given the safety of these old drugs, they may serve as promising candidates to treat the infection of SARS-CoV-2. Our results also provide rational explanations for the behaviour of five drugs evaluated in clinical trials.

Download Full-text

Gymnema Sylvestre A- Potential Inhibitor of COVID-19 Main Protease by MD Simulation Study

10.26434/chemrxiv.12333251 ◽

2020 ◽

Author(s):

Senthil Kumar Subramani ◽

Yash Gupta ◽

Manish Manish ◽

GBKS Prasad

Keyword(s):

Md Simulation ◽

Docking Study ◽

Binding Pocket ◽

Gymnema Sylvestre ◽

Molecular Docking Study ◽

Main Protease ◽

Strong Candidate ◽

The Stability ◽

Potential Inhibitors ◽

Domain I

Download Full-text

Glecaprevir and Maraviroc are high-affinity inhibitors of SARS-CoV-2 main protease: possible implication in COVID-19 therapy

Bioscience Reports ◽

10.1042/bsr20201256 ◽

2020 ◽

Vol 40 (6) ◽

Cited By ~ 24

Author(s):

Anas Shamsi ◽

Taj Mohammad ◽

Saleha Anwar ◽

Mohamed F. AlAjmi ◽

Afzal Hussain ◽

...

Keyword(s):

Substrate Binding ◽

Clinical Manifestations ◽

Binding Pocket ◽

Good Choice ◽

Sufficient Evidence ◽

Substrate Binding Pocket ◽

Structure Based Drug Design ◽

Main Protease ◽

Approved Drugs ◽

Fda Approved Drugs

Abstract Due to the lack of efficient therapeutic options and clinical trial limitations, the FDA-approved drugs can be a good choice to handle Coronavirus disease (COVID-19). Many reports have enough evidence for the use of FDA-approved drugs which have inhibitory potential against target proteins of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Here, we utilized a structure-based drug design approach to find possible drug candidates from the existing pool of FDA-approved drugs and checked their effectiveness against the SARS-CoV-2. We performed virtual screening of the FDA-approved drugs against the main protease (Mpro) of SARS-CoV-2, an essential enzyme, and a potential drug target. Using well-defined computational methods, we identified Glecaprevir and Maraviroc (MVC) as the best inhibitors of SARS-CoV-2 Mpro. Both drugs bind to the substrate-binding pocket of SARS-CoV-2 Mpro and form a significant number of non-covalent interactions. Glecaprevir and MVC bind to the conserved residues of substrate-binding pocket of SARS-CoV-2 Mpro. This work provides sufficient evidence for the use of Glecaprevir and MVC for the therapeutic management of COVID-19 after experimental validation and clinical manifestations.

Download Full-text

Natural Compounds as Inhibitors of SARS-CoV-2 Main Protease (3CLpro): A Molecular Docking and Simulation Approach to Combat COVID-19

Current Pharmaceutical Design ◽

10.2174/1381612826999201116195851 ◽

2020 ◽

Vol 26 ◽

Author(s):

Md Tabish Rehman ◽

Mohamed F. AlAjmi ◽

Afzal Hussain

Keyword(s):

Hydrophobic Interactions ◽

Rapid Development ◽

Economic Loss ◽

Binding Pocket ◽

Natural Compounds ◽

Active Site Residues ◽

Substrate Binding Pocket ◽

Reference Drug ◽

Drug Molecules ◽

Main Protease

Abstract:: The emergence and dissemination of SARS-CoV-2 has caused high mortality and enormous economic loss. Rapid development of new drug molecules is the need of hour to fight COVID-19. However, the conventional approaches of drug development are time consuming and expensive. Here, we have adopted a computational approach to identify lead molecules from nature. Ligands from natural compounds library available at Selleck Inc (L1400) have been screened for their ability to bind and inhibit the main protease (3CLpro) of SARS-CoV-2. We found that Kaempferol, Quercetin, and Rutin were bound at the substrate binding pocket of 3CLpro with high affinity (105-106 M-1) and interact with the active site residues such as His41 and Cys145 through hydrogen bonding and hydrophobic interactions. In fact, the binding affinity of Rutin (~106 M-1) was much higher than Chloroquine (~103 M-1) and Hydroxychloroquine (~104 M-1), and the reference drug Remdesivir (~105 M-1). The results suggest that natural compounds such as flavonoids have the potential to be developed as novel inhibitors of SARS-CoV-2 with a comparable/higher potency as that of Remdesivir. However, their clinical usage on COVID-19 patients is a subject of further investigations and clinical trials.

Download Full-text

Crystal structure of steroid reductase SRD5A reveals conserved steroid reduction mechanism

Nature Communications ◽

10.1038/s41467-020-20675-2 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Yufei Han ◽

Qian Zhuang ◽

Bo Sun ◽

Wenping Lv ◽

Sheng Wang ◽

...

Keyword(s):

Crystal Structure ◽

Biochemical Characterization ◽

Substrate Binding ◽

Binding Pocket ◽

Substrate Binding Pocket ◽

Transmembrane Segments ◽

Therapeutic Molecules ◽

Binding Cavity ◽

Immune System Regulation ◽

Mediated Reduction

AbstractSteroid hormones are essential in stress response, immune system regulation, and reproduction in mammals. Steroids with 3-oxo-Δ4 structure, such as testosterone or progesterone, are catalyzed by steroid 5α-reductases (SRD5As) to generate their corresponding 3-oxo-5α steroids, which are essential for multiple physiological and pathological processes. SRD5A2 is already a target of clinically relevant drugs. However, the detailed mechanism of SRD5A-mediated reduction remains elusive. Here we report the crystal structure of PbSRD5A from Proteobacteria bacterium, a homolog of both SRD5A1 and SRD5A2, in complex with the cofactor NADPH at 2.0 Å resolution. PbSRD5A exists as a monomer comprised of seven transmembrane segments (TMs). The TM1-4 enclose a hydrophobic substrate binding cavity, whereas TM5-7 coordinate cofactor NADPH through extensive hydrogen bonds network. Homology-based structural models of HsSRD5A1 and -2, together with biochemical characterization, define the substrate binding pocket of SRD5As, explain the properties of disease-related mutants and provide an important framework for further understanding of the mechanism of NADPH mediated steroids 3-oxo-Δ4 reduction. Based on these analyses, the design of therapeutic molecules targeting SRD5As with improved specificity and therapeutic efficacy would be possible.

Download Full-text