scholarly journals Drug Repurposing Against SARS-CoV-2 Using E-Pharmacophore Based Virtual Screening and Molecular Docking with Main Protease as the Target

2020 ◽  
Author(s):  
arun kumar ◽  
Sharanya C.S ◽  
Abhithaj J ◽  
Dileep Francis ◽  
Sadasivan C
Keyword(s):  
Free Energy ◽  
Molecular Docking ◽  
Drug Target ◽  
Binding Free Energy ◽  
Drug Repurposing ◽  
Energy Calculation ◽  
Viral Protease ◽  
Energy Estimation ◽  
Main Protease ◽  
Potential Inhibitors

Since its first report in December 2019 from China the COVID-19 pandemic caused by the beta-coronavirus SARS-CoV-2 has spread at an alarming pace infecting about 26 lakh, and claiming the lives of more than 1.8 lakh individuals across the globe. Although social quarantine measures have succeeded in containing the spread of the virus to some extent, the lack of a clinically approved vaccine or drug remains the biggest bottleneck in combating the pandemic. Drug repurposing can expedite the process of drug development by identifying known drugs which are effective against SARS-CoV-2. The SARS-CoV-2 main protease is a promising drug target due to its indispensable role in viral multiplication inside the host. In the present study an E-pharmacophore hypothesis was generated using the crystal structure of the viral protease in complex with an imidazole carbaximide inhibitor as the drug target. Drugs available in the superDRUG2 database were used to identify candidate drugs for repurposing. The hits were further screened using a structure based approach involving molecular docking at different precisions. The most promising drugs were subjected to binding free energy estimation using MM-GBSA. Among the 4600 drugs screened 17 drugs were identified as candidate inhibitors of the viral protease based on the glide scores obtained from molecular docking. Binding free energy calculation showed that six drugs viz, Binifibrate, Macimorelin acetate, Bamifylline, Rilmazafon, Afatinib and Ezetimibe can act as potential inhibitors of the viral protease.

scholarly journals Drug Repurposing Against SARS-CoV-2 Using E-Pharmacophore Based Virtual Screening and Molecular Docking with Main Protease as the Target

2020 ◽  
Author(s):  
arun kumar ◽  
Sharanya C.S ◽  
Abhithaj J ◽  
Dileep Francis ◽  
Sadasivan C
Keyword(s):  
Free Energy ◽  
Molecular Docking ◽  
Drug Target ◽  
Binding Free Energy ◽  
Drug Repurposing ◽  
Energy Calculation ◽  
Viral Protease ◽  
Energy Estimation ◽  
Main Protease ◽  
Potential Inhibitors

Since its first report in December 2019 from China the COVID-19 pandemic caused by the beta-coronavirus SARS-CoV-2 has spread at an alarming pace infecting about 26 lakh, and claiming the lives of more than 1.8 lakh individuals across the globe. Although social quarantine measures have succeeded in containing the spread of the virus to some extent, the lack of a clinically approved vaccine or drug remains the biggest bottleneck in combating the pandemic. Drug repurposing can expedite the process of drug development by identifying known drugs which are effective against SARS-CoV-2. The SARS-CoV-2 main protease is a promising drug target due to its indispensable role in viral multiplication inside the host. In the present study an E-pharmacophore hypothesis was generated using the crystal structure of the viral protease in complex with an imidazole carbaximide inhibitor as the drug target. Drugs available in the superDRUG2 database were used to identify candidate drugs for repurposing. The hits were further screened using a structure based approach involving molecular docking at different precisions. The most promising drugs were subjected to binding free energy estimation using MM-GBSA. Among the 4600 drugs screened 17 drugs were identified as candidate inhibitors of the viral protease based on the glide scores obtained from molecular docking. Binding free energy calculation showed that six drugs viz, Binifibrate, Macimorelin acetate, Bamifylline, Rilmazafon, Afatinib and Ezetimibe can act as potential inhibitors of the viral protease.

scholarly journals Computational Determination of Potential Inhibitors of SARS-CoV-2 Main Protease

2020 ◽  
Author(s):  
Son Tung Ngo ◽  
Ngoc Quynh Anh Pham ◽  
Ly Le ◽  
Duc-Hung Pham ◽  
Van Vu
Keyword(s):  
Free Energy ◽  
Molecular Docking ◽  
Drug Targets ◽  
Binding Free Energy ◽  
Natural Compounds ◽  
Main Protease ◽  
Energy Perturbation ◽  
Novel Coronavirus ◽  
Potential Inhibitors ◽  
Hiv 1

<p>The novel coronavirus (SARS-CoV-2) has infected over 850,000 people and caused more than 42000 deaths worldwide as of April 1<sup>st</sup>, 2020. As the disease is spreading rapidly all over the world, it is urgent to find effective drugs to treat the virus. The main protease (Mpro) of SARS-CoV-2 is one of the potential drug targets. In this work, we used rigorous computational methods, including molecular docking, fast pulling of ligand (FPL), and free energy perturbation (FEP), to investigate potential inhibitors of SARS-CoV-2 Mpro. We first tested our approach with three reported inhibitors of SARS-CoV-2 Mpro; and our computational results are in good agreement with the respective experimental data. Subsequently, we applied our approach on a databases of ~4600 natural compounds found in Vietnamese plants, as well as 8 available HIV-1 protease (PR) inhibitors and an aza-peptide epoxide. Molecular docking resulted in a short list of 35 natural compounds, which was subsequently refined using the FPL scheme. FPL simulations resulted in five potential inhibitors, including 3 natural compounds and two available HIV-1 PR inhibitors. Finally, FEP, the most accurate and precise method, was used to determine the absolute binding free energy of these five compounds. FEP results indicate that two natural compounds, <i>cannabisin </i>A and <i>isoacteoside</i>, and an HIV-1 PR inhibitor, <i>darunavir</i>, exhibit large binding free energy to SARS-CoV-2 Mpro, which is larger than that of <b>13b</b>, the most reliable SARS-CoV-2 Mpro inhibitor recently reported. The binding free energy largely arises from van der Waals (vdW) interaction. We also found that Glu166 form H-bonds to all the inhibitors. Replacing Glu166 by an alanine residue leads to ~ 2.0 kcal/mol decreases in the affinity of <i>darunavir </i>to SARS-CoV-2 Mpro. Our results could contribute to the development of potentials drugs inhibiting SARS-CoV-2. </p>

scholarly journals Computational Determination of Potential Inhibitors of SARS-CoV-2 Main Protease

2020 ◽  
Author(s):  
Son Tung Ngo ◽  
Ngoc Quynh Anh Pham ◽  
Ly Le ◽  
Duc-Hung Pham ◽  
Van Vu
Keyword(s):  
Free Energy ◽  
Molecular Docking ◽  
Drug Targets ◽  
Binding Free Energy ◽  
Natural Compounds ◽  
Main Protease ◽  
Energy Perturbation ◽  
Novel Coronavirus ◽  
Potential Inhibitors ◽  
Hiv 1

<p>The novel coronavirus (SARS-CoV-2) has infected over 850,000 people and caused more than 42000 deaths worldwide as of April 1<sup>st</sup>, 2020. As the disease is spreading rapidly all over the world, it is urgent to find effective drugs to treat the virus. The main protease (Mpro) of SARS-CoV-2 is one of the potential drug targets. In this work, we used rigorous computational methods, including molecular docking, fast pulling of ligand (FPL), and free energy perturbation (FEP), to investigate potential inhibitors of SARS-CoV-2 Mpro. We first tested our approach with three reported inhibitors of SARS-CoV-2 Mpro; and our computational results are in good agreement with the respective experimental data. Subsequently, we applied our approach on a databases of ~4600 natural compounds found in Vietnamese plants, as well as 8 available HIV-1 protease (PR) inhibitors and an aza-peptide epoxide. Molecular docking resulted in a short list of 35 natural compounds, which was subsequently refined using the FPL scheme. FPL simulations resulted in five potential inhibitors, including 3 natural compounds and two available HIV-1 PR inhibitors. Finally, FEP, the most accurate and precise method, was used to determine the absolute binding free energy of these five compounds. FEP results indicate that two natural compounds, <i>cannabisin </i>A and <i>isoacteoside</i>, and an HIV-1 PR inhibitor, <i>darunavir</i>, exhibit large binding free energy to SARS-CoV-2 Mpro, which is larger than that of <b>13b</b>, the most reliable SARS-CoV-2 Mpro inhibitor recently reported. The binding free energy largely arises from van der Waals (vdW) interaction. We also found that Glu166 form H-bonds to all the inhibitors. Replacing Glu166 by an alanine residue leads to ~ 2.0 kcal/mol decreases in the affinity of <i>darunavir </i>to SARS-CoV-2 Mpro. Our results could contribute to the development of potentials drugs inhibiting SARS-CoV-2. </p>

scholarly journals Assessing Potential Inhibitors for SARS-CoV-2 Main Protease from Available Drugs using Free Energy Perturbation Simulations

2020 ◽  
Author(s):  
Son Tung Ngo ◽  
Hung Minh Nguyen ◽  
Le Thi Thuy Huong ◽  
Pham Minh Quan ◽  
Vi Khanh Truong ◽  
...  
Keyword(s):  
Free Energy ◽  
Molecular Docking ◽  
Binding Affinity ◽  
Binding Free Energy ◽  
Accurate Method ◽  
Free Energy Perturbation ◽  
Main Protease ◽  
Energy Perturbation ◽  
Novel Coronavirus ◽  
Potential Inhibitors

<div> <p>The main protease (Mpro) of the novel coronavirus SARS-CoV-2, which causes the COVID-19 pandemic, is responsible for the maturation of its key proteins. Thus, inhibiting SARS-CoV-2 Mpro could prevent SARS-CoV-2 from multiplying. Because new inhibitors require thorough validation, repurposing current drugs could help reduce the validation process. Many recent studies used molecular docking to screen large databases for potential inhibitors of SARS-CoV-2 Mpro. However, molecular docking does not consider molecular dynamics and thus can be prone to error. In this work, we developed a protocol using free energy perturbation (FEP) to assess the potential inhibitors of SARS-CoV-2 Mpro. We first tested both molecular docking and FEP on a set of 11 inhibitors of SARS-CoV-2 Mpro with experimentally determined inhibitory data. The experimentally deduced binding free energy exhibits significantly stronger correlation with that predicted by FEP (R = 0.94 ± 0.04) than with that predicted by molecular docking (R = 0.82 ± 0.08). This result clearly shows that FEP is the most accurate method available to estimate the binding affinity of a ligand to SARS-CoV-2 Mpro. We subsequently used FEP to validate the top 33 compounds screened with molecular docking from the ZINC15 database. Thirteen of these compounds were predicted to have strong binding affinity for SARS-CoV-2 Mpro, most of which are currently used as drugs for various diseases in humans. Notably, delamanid, an anti-tuberculosis drug, was predicted to inhibit SARS-CoV-2 Mpro in the nanomolar range. Because both COVID-19 and tuberculosis are lung diseases, delamanid has higher probability to be suitable for treating COVID-19 than other predicted compounds. Analysis of the interactions between SARS-CoV-2 Mpro and the top inhibitors revealed the key residues involved in the binding, including the catalytic dyad His14 and Cys145, which is consistent with the structural studies reported recently.</p> </div> <br>

scholarly journals Assessing Potential Inhibitors for SARS-CoV-2 Main Protease from Available Drugs using Free Energy Perturbation Simulations

2020 ◽  
Author(s):  
Son Tung Ngo ◽  
Hung Minh Nguyen ◽  
Le Thi Thuy Huong ◽  
Pham Minh Quan ◽  
Vi Khanh Truong ◽  
...  
Keyword(s):  
Free Energy ◽  
Molecular Docking ◽  
Binding Affinity ◽  
Binding Free Energy ◽  
Accurate Method ◽  
Free Energy Perturbation ◽  
Main Protease ◽  
Energy Perturbation ◽  
Novel Coronavirus ◽  
Potential Inhibitors

<div> <p>The main protease (Mpro) of the novel coronavirus SARS-CoV-2, which causes the COVID-19 pandemic, is responsible for the maturation of its key proteins. Thus, inhibiting SARS-CoV-2 Mpro could prevent SARS-CoV-2 from multiplying. Because new inhibitors require thorough validation, repurposing current drugs could help reduce the validation process. Many recent studies used molecular docking to screen large databases for potential inhibitors of SARS-CoV-2 Mpro. However, molecular docking does not consider molecular dynamics and thus can be prone to error. In this work, we developed a protocol using free energy perturbation (FEP) to assess the potential inhibitors of SARS-CoV-2 Mpro. We first tested both molecular docking and FEP on a set of 11 inhibitors of SARS-CoV-2 Mpro with experimentally determined inhibitory data. The experimentally deduced binding free energy exhibits significantly stronger correlation with that predicted by FEP (R = 0.94 ± 0.04) than with that predicted by molecular docking (R = 0.82 ± 0.08). This result clearly shows that FEP is the most accurate method available to estimate the binding affinity of a ligand to SARS-CoV-2 Mpro. We subsequently used FEP to validate the top 33 compounds screened with molecular docking from the ZINC15 database. Thirteen of these compounds were predicted to have strong binding affinity for SARS-CoV-2 Mpro, most of which are currently used as drugs for various diseases in humans. Notably, delamanid, an anti-tuberculosis drug, was predicted to inhibit SARS-CoV-2 Mpro in the nanomolar range. Because both COVID-19 and tuberculosis are lung diseases, delamanid has higher probability to be suitable for treating COVID-19 than other predicted compounds. Analysis of the interactions between SARS-CoV-2 Mpro and the top inhibitors revealed the key residues involved in the binding, including the catalytic dyad His14 and Cys145, which is consistent with the structural studies reported recently.</p> </div> <br>

scholarly journals Computational Determination of Potential Inhibitors of SARS-CoV-2 Main Protease

2020 ◽  
Author(s):  
Son Tung Ngo ◽  
Ngoc Quynh Anh Pham ◽  
Ly Le ◽  
Duc-Hung Pham ◽  
Van Vu
Keyword(s):  
Free Energy ◽  
Molecular Docking ◽  
Drug Targets ◽  
Binding Free Energy ◽  
Natural Compounds ◽  
Main Protease ◽  
Energy Perturbation ◽  
Novel Coronavirus ◽  
Potential Inhibitors ◽  
Hiv 1

<p>The novel coronavirus (SARS-CoV-2) has infected over 850,000 people and caused more than 42000 deaths worldwide as of April 1<sup>st</sup>, 2020. As the disease is spreading rapidly all over the world, it is urgent to find effective drugs to treat the virus. The main protease (Mpro) of SARS-CoV-2 is one of the potential drug targets. In this work, we used rigorous computational methods, including molecular docking, fast pulling of ligand (FPL), and free energy perturbation (FEP), to investigate potential inhibitors of SARS-CoV-2 Mpro. We first tested our approach with three reported inhibitors of SARS-CoV-2 Mpro; and our computational results are in good agreement with the respective experimental data. Subsequently, we applied our approach on a databases of ~4600 natural compounds found in Vietnamese plants, as well as 8 available HIV-1 protease (PR) inhibitors and an aza-peptide epoxide. Molecular docking resulted in a short list of 35 natural compounds, which was subsequently refined using the FPL scheme. FPL simulations resulted in five potential inhibitors, including 3 natural compounds and two available HIV-1 PR inhibitors. Finally, FEP, the most accurate and precise method, was used to determine the absolute binding free energy of these five compounds. FEP results indicate that two natural compounds, <i>cannabisin </i>A and <i>isoacteoside</i>, and an HIV-1 PR inhibitor, <i>darunavir</i>, exhibit large binding free energy to SARS-CoV-2 Mpro, which is larger than that of <b>13b</b>, the most reliable SARS-CoV-2 Mpro inhibitor recently reported. The binding free energy largely arises from van der Waals (vdW) interaction. We also found that Glu166 form H-bonds to all the inhibitors. Replacing Glu166 by an alanine residue leads to ~ 2.0 kcal/mol decreases in the affinity of <i>darunavir </i>to SARS-CoV-2 Mpro. Our results could contribute to the development of potentials drugs inhibiting SARS-CoV-2. </p>

Current Trends in Docking Methodologies

Oncology ◽  
2017 ◽  
pp. 829-847
Author(s):  
Shubhandra Tripathi ◽  
Akhil Kumar ◽  
Amandeep Kaur Kahlon ◽  
Ashok Sharma
Keyword(s):  
Free Energy ◽  
Molecular Docking ◽  
Binding Affinity ◽  
Binding Free Energy ◽  
Energy Calculation ◽  
Molecular Binding ◽  
New Horizons ◽  
Current Trends ◽  
Complex Scheme ◽  
Dynamics Simulations

Molecular docking was earlier considered to predict the binding affinity of the receptor and ligand molecules. With the progress in computational power and developing approaches, new horizons are now opening for accurate prediction of molecular binding affinity. In the current book chapter, recent strategies for Computer-Aided Drug Designing (CADD) including virtual screening and molecular docking, encompassing molecular dynamics simulations, and binding free energy calculation methods are discussed. Brief overview of different binding free energy methods MMPBSA, MMGBSA, LIE and TI have also been given along with the recent Relaxed Complex Scheme protocol.

scholarly journals Potential of Plant Bioactive Compounds as SARS-CoV-2 Main Protease (Mpro) and Spike (S) Glycoprotein Inhibitors: A Molecular Docking Study

2020 ◽  
Author(s):  
Trina Ekawati Tallei ◽  
Sefren Geiner Tumilaar ◽  
Nurdjannah Jane Niode ◽  
Fatimawali Fatimawali ◽  
Billy Johnson Kepel ◽  
...  
Keyword(s):  
Free Energy ◽  
Molecular Docking ◽  
Bioactive Compounds ◽  
Binding Free Energy ◽  
Epigallocatechin Gallate ◽  
Docking Study ◽  
Molecular Docking Study ◽  
Ligand Complex ◽  
Main Protease ◽  
Glycoprotein Inhibitors

Since the outbreak of the COVID-19 (Coronavirus Disease 19) pandemic, researchers have been trying to investigate several active compounds found in plants that have the potential to inhibit the proliferation of SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2). The present study aimed to evaluate bioactive compounds found in plants by using a molecular docking approach to inhibit the Main Protease (Mpro) and Spike (S) glycoprotein of SARS-CoV-2. The evaluation was performed on the docking scores calculated using AutoDock Vina as a docking engine. A rule of five (RO5) was calculated to determine whether a compound meets the criteria as an active drug orally in humans. The determination of the docking score was done by selecting the best conformation of the protein-ligand complex that had the highest affinity (most negative Gibbs' free energy of binding / &Delta;G). As a comparison, nelfinavir (an antiretroviral drug), chloroquine and hydroxychloroquine sulfate (anti-malarial drugs recommended by the FDA as emergency drugs) were used. The results showed that hesperidin, nabiximols, pectolinarin, epigallocatechin gallate, and rhoifolin had better poses than nelfinavir, chloroquine, and hydroxychloroquine sulfate as spike glycoprotein inhibitors. Hesperidin, rhoifolin, pectolinarin, and nabiximols had about the same pose as nelfinavir, but were better than chloroquine and hydroxychloroquine sulfate as Mpro inhibitors. These plant compounds have the potential to be developed as specific therapeutic agents against COVID-19. Several natural compounds of plants evaluated in this study showed better binding free energy compared to nelfinavir, chloroquine, and hydroxychloroquine sulfate which so far are recommended in the treatment of COVID-19. As judged by the RO5 and previous study by others, the compounds kaempferol, herbacetin, eugenol, and 6-shogaol have good oral bioavailability, so they are also seen as promising candidates for the development lead compounds to treat infections caused by SARS-CoV-2.

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