In Silico Molecular Dynamics Docking of Drugs to the Inhibitory Active Site of SARS-CoV-2 Protease and Their Predicted Toxicology and ADME

A in silico molecular dynamics (MD) docking investigation was conducted to identify drugs (ligands) which could potentially be of interest for repurposing. We sought ligands which formed the strongest binding potential energy with the x-ray crystallography-based active site of the SARS-CoV-2 protease C3Lpro. A total of 11,013 ligands were obtained from DrugBank. Because of the larger size of the active site of 3CLpro, we chose ligands whose molecular weight (MW) was greater than 400 (daltons) and less than 700, which resulted in 5,920 ligands. After correction of bonds and hydrogens, there were 4,634 ligands available for docking. Docking results indicate that the top 10 investigational and experimental drugs with binding energy (BE)≤-9 kcal/mol were Lorecivivint, Tivantinib, Omipalisib, DrugBank B08450, SRT-2104, R-428, DrugBank B01897, Bictegravir, Ridinilazole, and Itacitinib, while the top 10 approved drugs with BE≤-8.2 were Olaparib, Etoposide, Ouabain, Indinavir, Idelalisib, Trametinib, Lumacaftor, Ergotamine, Canagliflozin, and Edoxaban. There were two antiviral drugs among the top 30 hits, which were Bictegravir (investigational) and Indinavir (approved). The top 10 antivirals with BE≤-8.2 were Bictegravir, Tegobuvir, Filibuvir, Saquinavir, Fostemsavir, Indinavir, Temsavir, Pimodivir, Amenamevir, and Doravirine. Interestingly, the antiviral Remdesavir ranked low among the top 30 antivirals, since its BE was a low value of -7.5 kcal/mol. In silico toxicology and ADME (absorption, distribution, metabolism, excretion) prediction indicates that only 20% (6/30) of the top ligands were “drug-like,” and none were “lead-like,” since the lower bound of MW was 400. Another interesting finding was that the investigational natural supplement Diosmin (DrugBank ID B08995), used without prescription for varicose veins, ranked 22 overall (out of 3,896 with BE≤-6) with a strong BE=-8.8, and formed 8 hydrogen bonds with the active site for the putative best pose. Its energy-minimized 3D structure deeply penetrated and fully covered the width of the active site’s pocket. Diosmin had a lower BE than 97% of the top 30 antiviral drugs and formed more hydrogen bonds with the active site than 93% of the top 30 antivirals. Diosmin could therefore potentially serve as a strong inhibitor of the 3CLpro protease of SARS-CoV-2 and could be investigated in human clinical trials. Since a prescription is not required for its use, it could also be explored as a self-medicating natural alternative to prescribed synthetic drugs. Lastly, the green tea component epigallocatechin gallate (DrugBank ID B12116) also had a low BE=-8.3, and formed 2 hydrogen bonds with the active site, which was a BE that was better than 70% of the top 30 antivirals.

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In Silico Molecular Dynamics Docking of Drugs to the Inhibitory Active Site of SARS-CoV-2 Protease and Their Predicted Toxicology and ADME

10.26434/chemrxiv.12155523.v1 ◽

2020 ◽

Cited By ~ 3

Author(s):

Leif Peterson

Keyword(s):

Molecular Dynamics ◽

Hydrogen Bonds ◽

Active Site ◽

In Silico ◽

Varicose Veins ◽

3D Structure ◽

Antiviral Drugs ◽

Binding Potential ◽

Strong Inhibitor ◽

Experimental Drugs

A in silico molecular dynamics (MD) docking investigation was conducted to identify drugs (ligands) which could potentially be of interest for repurposing. We sought ligands which formed the strongest binding potential energy with the x-ray crystallography-based active site of the SARS-CoV-2 protease C3Lpro. A total of 11,013 ligands were obtained from DrugBank. Because of the larger size of the active site of 3CLpro, we chose ligands whose molecular weight (MW) was greater than 400 (daltons) and less than 700, which resulted in 5,920 ligands. After correction of bonds and hydrogens, there were 4,634 ligands available for docking. Docking results indicate that the top 10 investigational and experimental drugs with binding energy (BE)≤-9 kcal/mol were Lorecivivint, Tivantinib, Omipalisib, DrugBank B08450, SRT-2104, R-428, DrugBank B01897, Bictegravir, Ridinilazole, and Itacitinib, while the top 10 approved drugs with BE≤-8.2 were Olaparib, Etoposide, Ouabain, Indinavir, Idelalisib, Trametinib, Lumacaftor, Ergotamine, Canagliflozin, and Edoxaban. There were two antiviral drugs among the top 30 hits, which were Bictegravir (investigational) and Indinavir (approved). The top 10 antivirals with BE≤-8.2 were Bictegravir, Tegobuvir, Filibuvir, Saquinavir, Fostemsavir, Indinavir, Temsavir, Pimodivir, Amenamevir, and Doravirine. Interestingly, the antiviral Remdesavir ranked low among the top 30 antivirals, since its BE was a low value of -7.5 kcal/mol. In silico toxicology and ADME (absorption, distribution, metabolism, excretion) prediction indicates that only 20% (6/30) of the top ligands were “drug-like,” and none were “lead-like,” since the lower bound of MW was 400. Another interesting finding was that the investigational natural supplement Diosmin (DrugBank ID B08995), used without prescription for varicose veins, ranked 22 overall (out of 3,896 with BE≤-6) with a strong BE=-8.8, and formed 8 hydrogen bonds with the active site for the putative best pose. Its energy-minimized 3D structure deeply penetrated and fully covered the width of the active site’s pocket. Diosmin had a lower BE than 97% of the top 30 antiviral drugs and formed more hydrogen bonds with the active site than 93% of the top 30 antivirals. Diosmin could therefore potentially serve as a strong inhibitor of the 3CLpro protease of SARS-CoV-2 and could be investigated in human clinical trials. Since a prescription is not required for its use, it could also be explored as a self-medicating natural alternative to prescribed synthetic drugs. Lastly, the green tea component epigallocatechin gallate (DrugBank ID B12116) also had a low BE=-8.3, and formed 2 hydrogen bonds with the active site, which was a BE that was better than 70% of the top 30 antivirals.

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Synthesis and In-silico Studies of C-4 Substituted Coumarin Analogues as Anticancer Agents

Current Computer - Aided Drug Design ◽

10.2174/1573409916666200628104638 ◽

2020 ◽

Vol 16 ◽

Author(s):

Jyoti Dandriyal ◽

Kamalpreet Kaur ◽

Vikas Jaitak

Keyword(s):

Anticancer Agents ◽

Active Site ◽

In Silico ◽

Oral Absorption ◽

In Vivo Studies ◽

Conventional Heating ◽

Microwave Assisted Synthesis ◽

Standard Drug ◽

In Silico Studies ◽

Adme Properties

Background: Coumarin is a fused ring system and possesses enormous capability of targeting various receptors participating in cancer pathway. Coumarin and its derivatives were found to exhibit very rare toxicity and other side effects. It has been found its immense anticancer potential depends on the nature of group present and its pattern of substitution on the basic nucleus. Objectives: Synthesis of C-4 substituted coumarin derivatives and to study their molecular interactions with ERα for anticancer activity for Breast Cancer. Method: C-4 substituted coumarins analogues (1-10) have been synthesized using conventional heating and microwave irradiation. Using Schrodinger software molecular modeling studies were carried out and ADME properties of the compounds were predicted. Results: All the synthesized compounds have shown better G-Score (-6.87 to -8.43 kcal/mol) as compared to the standard drug tamoxifen (-5.28kcal/mol) and auraptene (-3.89kcal/mol). Molecular docking suggests that all compounds fit in the active site of protein as they have the same hydrophobic pocket as standard drug tamoxifen, and have an acceptable range of ADME properties. Conclusion: Microwave-assisted synthesis showed better results as compared to conventional heating. In-silico studies revealed that all the compounds befit in the active site of protein. ADME properties showed that all compounds are in allowable limits for human oral absorption. In future, there is a possibility of in-vitro and in-vivo studies of the synthesized compounds.

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In silico design of novel diamino-quinoline-5,8-dione derivatives as putative inhibitors of NAD(P)H:Quinone Oxidoreductase 1 based on docking studies and molecular dynamics simulations

Journal of Molecular Structure ◽

10.1016/j.molstruc.2021.129906 ◽

2021 ◽

pp. 129906

Author(s):

Maryam Gholampour ◽

Amirhossein Sakhteman ◽

Somayeh Pirhadi ◽

Hassan Seradj

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulations ◽

In Silico ◽

Docking Studies ◽

In Silico Design ◽

Dynamics Simulations

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WHICH IS THE PROTON-SHUTTLE IN ISOXANTHOPTERIN DEAMINASE? QM/MM MD UNDERSTANDING

Journal of Theoretical and Computational Chemistry ◽

10.1142/s0219633613410022 ◽

2013 ◽

Vol 12 (08) ◽

pp. 1341002 ◽

Cited By ~ 1

Author(s):

XIN ZHANG ◽

MING LEI

Keyword(s):

Crystal Structure ◽

Molecular Dynamics ◽

Hydrogen Bonds ◽

Proton Transfer ◽

Glutamic Acid ◽

Active Site ◽

Nucleophilic Attack ◽

Zinc Ions ◽

Initial Model ◽

Dynamics Simulations

The deamination process of isoxanthopterin catalyzed by isoxanthopterin deaminase was determined using the combined QM(PM3)/MM molecular dynamics simulations. In this paper, the updated PM3 parameters were employed for zinc ions and the initial model was built up based on the crystal structure. Proton transfer and following steps have been investigated in two paths: Asp336 and His285 serve as the proton shuttle, respectively. Our simulations showed that His285 is more effective than Aap336 in proton transfer for deamination of isoxanthopterin. As hydrogen bonds between the substrate and surrounding residues play a key role in nucleophilic attack, we suggested mutating Thr195 to glutamic acid, which could enhance the hydrogen bonds and help isoxanthopterin get close to the active site. The simulations which change the substrate to pterin 6-carboxylate also performed for comparison. Our results provide reference for understanding of the mechanism of deaminase and for enhancing the deamination rate of isoxanthopterin deaminase.

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