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

2020 ◽  
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

<p></p><p>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.</p><p></p>

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

2020 ◽  
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

<p></p><p>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.</p><p></p>

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

2013 ◽  
Vol 12 (08) ◽  
pp. 1341002 ◽  
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.

scholarly journals AKTIVITAS AGEN PENCERAH KULIT DARI KATEKIN SECARA IN SILICO

Jurnal Kimia ◽  
2019 ◽  
pp. 196
Author(s):  
N. K. M. Giantari ◽  
I W. I. Prayoga ◽  
N. P. L. Laksmiani
Keyword(s):  
Molecular Docking ◽  
Hydrogen Bonds ◽  
Bond Energy ◽  
In Silico ◽  
3D Structure ◽  
Related Protein ◽  
Protein Preparation ◽  
Energy Value ◽  
Skin Lightening ◽  
Tyrosinase Related Protein

Darkening of the skin results from excessive production of melanin in the skin caused by an increase in tyrosinase related protein 1 enzyme activity. Catechins are flavonoid compounds which contain antioxidants. This study aims to determine the affinity and mechanism of catechins as skin lightening agents by inhibiting tyrosinase related protein 1 target proteins in silico using molecular docking methods. The study was carried out exploratively with the stages of preparing a database of 3D structures of catechins and tyrosinase related protein 1, optimization of 3D structure of catechins, protein preparation, validation of molecular docking methods, and docking of catechins in tyrosinase related protein 1. Docking results are assessed from the bonding energy and hydrogen bonds formed between catechins and proteins. The smaller the bond energy value, the stronger the bond between the catechins and proteins. The results showed that catechins had activity as skin lightening agents because they were able to inhibit the tyrosinase related protein 1 with a bond energy value of -6,35 Kcal/mol. The energy value of the catechin bond with the tyrosinase related protein 1 is smaller than the tyrosinase related protein 1 with its native ligand. This shows that catechins have greater potential and affinity in inhibiting the tyrosinase related protein 1 enzyme with hydrogen bonds on amino acid residues, namely ARG374. Based on the results obtained, catechins have activity as skin lightening agents with the mechanism of inhibiting the tyrosinase related protein 1 enzyme so that the amount of eumelanin formed is less and the skin becomes brighter. Key words: catechins, skin lightening, tyrosinase related protein 1, in silico, molecular docking

scholarly journals In silico characterization of the NiRAN domain of RNA-dependent RNA polymerase provides insights into a potential therapeutic target against SARS-CoV2

2020 ◽  
Author(s):  
Abhisek Dwivedy ◽  
Richard Mariadasse ◽  
Mohammed Ahmed ◽  
Deepsikha Kar ◽  
Jeyaraman Jeyakanthan ◽  
...  
Keyword(s):  
Active Site ◽  
In Silico ◽  
3D Structure ◽  
Drug Repurposing ◽  
The Novel ◽  
Lead Compounds ◽  
Nucleotidyl Transferase ◽  
Domain Organisation ◽  
Novel Coronavirus ◽  
In Silico Characterization

Apart from the canonical fingers, palm and thumb domains, the RNA dependent RNA polymerases (RdRp) from the viral order Nidovirales possess two additional domains. Of these, the function of the Nidovirus RdRp associated nucleotidyl transferase domain (NiRAN) remains unanswered. The elucidation of the 3D structure of the RdRp from the novel coronavirus – SARS-CoV2, provided the first ever insights into the domain organisation and possible functional characteristics of the NiRAN domain. Using in silico tools, this study predicts that the NiRAN domain assumes a kinase or phosphotransferase like fold and binds GTP and UTP at its proposed active site. Additionally, using molecular docking this study predicts the binding of five well characterized anti-microbial compounds at the NiRAN domain active site and their drug-likeliness and DFT properties. In line with the current global COVID-19 pandemic urgency, this study provides a new target and potential lead compounds for drug repurposing against SARS-CoV2.

scholarly journals Molecular Mechanisms on the Selectivity Enhancement of Ascorbic Acid, Dopamine, and Uric Acid by Serine Oligomers Decoration on Graphene Oxide: A Molecular Dynamics Study

Molecules ◽  
2021 ◽  
Vol 26 (10) ◽  
pp. 2876
Author(s):  
Threrawee Sanglaow ◽  
Pattanan Oungkanitanon ◽  
Piyapong Asanithi ◽  
Thana Sutthibutpong
Keyword(s):  
Molecular Dynamics ◽  
Ascorbic Acid ◽  
Uric Acid ◽  
Graphene Oxide ◽  
Hydrogen Bonds ◽  
In Silico ◽  
Molecular Mechanisms ◽  
Simultaneous Detection

The selectivity in the simultaneous detection of ascorbic acid (AA), dopamine (DA), and uric acid (UA) has been an open problem in the biosensing field. Many surface modification methods were carried out for glassy carbon electrodes (GCE), including the use of graphene oxide and amino acids as a selective layer. In this work, molecular dynamics (MD) simulations were performed to investigate the role of serine oligomers on the selectivity of the AA, DA, and UA analytes. Our models consisted of a graphene oxide (GO) sheet under a solvent environment. Serine tetramers were added into the simulation box and were adsorbed on the GO surface. Then, the adsorption of each analyte on the mixed surface was monitored from MD trajectories. It was found that the adsorption of AA was preferred by serine oligomers due to the largest number of hydrogen-bond forming functional groups of AA, causing a 10-fold increase of hydrogen bonds by the tetraserine adsorption layer. UA was the least preferred due to its highest aromaticity. Finally, the role of hydrogen bonds on the electron transfer selectivity of biosensors was discussed with some previous studies. AA radicals received electrons from serine through hydrogen bonds that promoted oxidation reaction and caused the negative shifts and separation of the oxidation potential in experiments, as DA and UA were less affected by serine. Agreement of the in vitro and in silico results could lead to other in silico designs of selective layers to detect other types of analyte molecules.

scholarly journals Alkaloids from Cryptolepis sanguinolenta as Potential Inhibitors of SARS-CoV-2 Viral Proteins: An In Silico Study

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Lawrence Sheringham Borquaye ◽  
Edward Ntim Gasu ◽  
Gilbert Boadu Ampomah ◽  
Lois Kwane Kyei ◽  
Margaret Amerley Amarh ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Rna Polymerase ◽  
In Silico ◽  
Viral Proteins ◽  
Binding Energies ◽  
New Drugs ◽  
Binding Potential ◽  
Rna Dependent Rna Polymerase ◽  
Cryptolepis Sanguinolenta ◽  
Main Protease

The ongoing global pandemic caused by the human coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected millions of people and claimed hundreds of thousands of lives. The absence of approved therapeutics to combat this disease threatens the health of all persons on earth and could cause catastrophic damage to society. New drugs are therefore urgently required to bring relief to people everywhere. In addition to repurposing existing drugs, natural products provide an interesting alternative due to their widespread use in all cultures of the world. In this study, alkaloids from Cryptolepis sanguinolenta have been investigated for their ability to inhibit two of the main proteins in SARS-CoV-2, the main protease and the RNA-dependent RNA polymerase, using in silico methods. Molecular docking was used to assess binding potential of the alkaloids to the viral proteins whereas molecular dynamics was used to evaluate stability of the binding event. The results of the study indicate that all 13 alkaloids bind strongly to the main protease and RNA-dependent RNA polymerase with binding energies ranging from -6.7 to -10.6 kcal/mol. In particular, cryptomisrine, cryptospirolepine, cryptoquindoline, and biscryptolepine exhibited very strong inhibitory potential towards both proteins. Results from the molecular dynamics study revealed that a stable protein-ligand complex is formed upon binding. Alkaloids from Cryptolepis sanguinolenta therefore represent a promising class of compounds that could serve as lead compounds in the search for a cure for the corona virus disease.

scholarly journals Human hydroxymethylbilane synthase: Molecular dynamics of the pyrrole chain elongation identifies step-specific residues that cause AIP

2018 ◽  
Vol 115 (17) ◽  
pp. E4071-E4080 ◽  
Author(s):  
Navneet Bung ◽  
Arijit Roy ◽  
Brenden Chen ◽  
Dibyajyoti Das ◽  
Meenakshi Pradhan ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Active Site ◽  
3D Structure ◽  
Acute Intermittent Porphyria ◽  
Md Simulations ◽  
Chain Elongation ◽  
Active Site Residues ◽  
Autosomal Dominant Disorder ◽  
Random Acceleration

Hydroxymethylbilane synthase (HMBS), the third enzyme in the heme biosynthetic pathway, catalyzes the head-to-tail condensation of four molecules of porphobilinogen (PBG) to form the linear tetrapyrrole 1-hydroxymethylbilane (HMB). Mutations in human HMBS (hHMBS) cause acute intermittent porphyria (AIP), an autosomal-dominant disorder characterized by life-threatening neurovisceral attacks. Although the 3D structure of hHMBS has been reported, the mechanism of the stepwise polymerization of four PBG molecules to form HMB remains unknown. Moreover, the specific roles of each of the critical active-site residues in the stepwise enzymatic mechanism and the dynamic behavior of hHMBS during catalysis have not been investigated. Here, we report atomistic studies of HMB stepwise synthesis by using molecular dynamics (MD) simulations, mutagenesis, and in vitro expression analyses. These studies revealed that the hHMBS active-site loop movement and cofactor turn created space for the elongating pyrrole chain. Twenty-seven residues around the active site and water molecules interacted to stabilize the large, negatively charged, elongating polypyrrole. Mutagenesis of these active-site residues altered the binding site, hindered cofactor binding, decreased catalysis, impaired ligand exit, and/or destabilized the enzyme. Based on intermediate stages of chain elongation, R26 and R167 were the strongest candidates for proton transfer to deaminate the incoming PBG molecules. Unbiased random acceleration MD simulations identified R167 as a gatekeeper and facilitator of HMB egress through the space between the enzyme’s domains and the active-site loop. These studies identified the specific active-site residues involved in each step of pyrrole elongation, thereby providing the molecular bases of the active-site mutations causing AIP.

scholarly journals IN-SILICO ANALYSIS

2016 ◽  
Vol 23 (02) ◽  
pp. 217-222
Author(s):  
Hammad Tufail Chaudhary ◽  
Shahida Hasnain
Keyword(s):  
Hydrogen Bonds ◽  
Active Site ◽  
In Silico ◽  
Active Sites ◽  
In Silico Analysis ◽  
Data Bank ◽  
Protein Data Bank Code ◽  
In Silico Study ◽  
Study Setting ◽  
Silico Analysis

ntroduction: Different pathogen reducing technologies are being implementedwhich includes S-303. CD-61 is important receptor for clotting. Pathogen reducing agents arebeing studied extensively to probe its effects. Objective: We conducted this study to reviewthe docking of S-303 at CD-61, to look into the effect of S-303 on function of platelets. StudyDesign: This was an observational study. Setting: In-silico study. Period: March 2015 toAugust 2015. Method: The study was carried out in-silico. PDB (Protein data bank) code ofTirofiban bound to CD-61 was 2vdm. CD-61 was docked with Tirofiban using online dockingtools i.e. Patchdock and Firedock. Then, S-303 and CD-61 were also docked. Best dockingposes to active sites of 2vdm were found. Interactions of ligands and CD-61 were obtained.Then comparison of Hydrogen Bonds, Hydrogen Bond Lengths, Hydrophobic bonds of 2vdmmolecule and best poses of docking results were done. Patchdock and Firdock results of bestposes were also analyzed using SPSS-16. Results: The Hydrogen bonds and Hydrogen bondlength and hydrophobic bonds of docking results were compared to 2vdm. 2 best poses wereobtained for docking of tirofiban to CD-61. No docking to active site was observed in Patchdockand firedock for S-303to CD-61. Conclusion: S-303 did not bind to the active site of CD-61. Wecan assume that S-303 doe

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