scholarly journals Insight Derived from Molecular Docking and Molecular Dynamics Simulations into the Binding Interactions Between HIV-1 Protease Inhibitors and SARS-CoV-2 3CLpro

2020 ◽  
Author(s):  
peng sang ◽  
Shuhui Tian ◽  
Zhaohui Meng ◽  
Liquan Yang
Keyword(s):  
Molecular Docking ◽  
Protease Inhibitors ◽  
Binding Affinity ◽  
Proteinase Inhibitors ◽  
Binding Free Energy ◽  
Md Simulations ◽  
Respiratory Illness ◽  
Free Energy Calculations ◽  
Binding Interactions ◽  
Hiv 1

<p>A novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) was identified from respiratory illness patients in Wuhan, Hubei Province, China, which has recently emerged as a serious threat to the world public health. Hower, no approved drugs have been found to effectively inhibit the virus. Since it has been reported that the HIV-1 protease inhibitors can be used as anti-SARS drugs by tegarting SARS-CoV 3CLpro, we choose six approved anti-HIV-1 drugs to investigate their binding interactions between 3CLpro, and to evaluate their potential to become clinical drugs for the new coronavirus pneumonia (COVID19) caused by SARS-CoV-2 infection. The molecular docking results indicate that, the 3CLpro of SARS-CoV-2 has a higher binding affinity for all the studied inhibitors than its SARS homologue. Two docking complexes (indinavir and darunavir) with high docking scores were futher subjected to MM-PBSA binding free energy calculations to detail the molecular interactions between these two proteinase inhibitors and the 3CLpro. Our results show that darunavir has the best binding affinity with SARS-CoV-2 and SARS-CoV 3CLpro among all inhibitors, indicating it has the potential to become an anti-COVID-19 clinical drug. The likely reason behind the increased binding affinity of HIV-1 protease inhibitors toward SARS-CoV2 3CLpro than that of SARS-CoV were investigated by MD simulations. Our study provides insight into the possible role of structural flexibility during interactions between 3CLpro and inhibitors, and sheds light on the structure-based design of anti-COVID-19 drugs targeting the SARS-CoV-2 3CLpro. </p><div><br></div>

scholarly journals Insight Derived from Molecular Docking and Molecular Dynamics Simulations into the Binding Interactions Between HIV-1 Protease Inhibitors and SARS-CoV-2 3CLpro

2020 ◽  
Author(s):  
peng sang ◽  
Shuhui Tian ◽  
Zhaohui Meng ◽  
Liquan Yang
Keyword(s):  
Molecular Docking ◽  
Protease Inhibitors ◽  
Binding Affinity ◽  
Proteinase Inhibitors ◽  
Binding Free Energy ◽  
Md Simulations ◽  
Respiratory Illness ◽  
Free Energy Calculations ◽  
Binding Interactions ◽  
Hiv 1

<p>A novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) was identified from respiratory illness patients in Wuhan, Hubei Province, China, which has recently emerged as a serious threat to the world public health. Hower, no approved drugs have been found to effectively inhibit the virus. Since it has been reported that the HIV-1 protease inhibitors can be used as anti-SARS drugs by tegarting SARS-CoV 3CLpro, we choose six approved anti-HIV-1 drugs to investigate their binding interactions between 3CLpro, and to evaluate their potential to become clinical drugs for the new coronavirus pneumonia (COVID19) caused by SARS-CoV-2 infection. The molecular docking results indicate that, the 3CLpro of SARS-CoV-2 has a higher binding affinity for all the studied inhibitors than its SARS homologue. Two docking complexes (indinavir and darunavir) with high docking scores were futher subjected to MM-PBSA binding free energy calculations to detail the molecular interactions between these two proteinase inhibitors and the 3CLpro. Our results show that darunavir has the best binding affinity with SARS-CoV-2 and SARS-CoV 3CLpro among all inhibitors, indicating it has the potential to become an anti-COVID-19 clinical drug. The likely reason behind the increased binding affinity of HIV-1 protease inhibitors toward SARS-CoV2 3CLpro than that of SARS-CoV were investigated by MD simulations. Our study provides insight into the possible role of structural flexibility during interactions between 3CLpro and inhibitors, and sheds light on the structure-based design of anti-COVID-19 drugs targeting the SARS-CoV-2 3CLpro. </p><div><br></div>

scholarly journals In Silico Exploration of Phytoconstituents From Phyllanthus emblica and Aegle marmelos as Potential Therapeutics Against SARS-CoV-2 RdRp

2021 ◽  
Vol 15 ◽  
pp. 117793222110274
Author(s):  
Khushboo Pandey ◽  
Kiran Bharat Lokhande ◽  
K Venkateswara Swamy ◽  
Shuchi Nagar ◽  
Manjusha Dake
Keyword(s):  
Molecular Docking ◽  
Binding Affinity ◽  
Simulation Analysis ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Molecular Field ◽  
Hydroxyl Groups ◽  
Phyllanthus Emblica ◽  
Inhibitory Potential ◽  
Novel Drug

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) worldwide has increased the importance of computational tools to design a drug or vaccine in reduced time with minimum risk. Earlier studies have emphasized the important role of RNA-dependent RNA polymerase (RdRp) in SARS-CoV-2 replication as a potential drug target. In our study, comprehensive computational approaches were applied to identify potential compounds targeting RdRp of SARS-CoV-2. To study the binding affinity and stability of the phytocompounds from Phyllanthus emblica and Aegel marmelos within the defined binding site of SARS-CoV-2 RdRp, they were subjected to molecular docking, 100 ns molecular dynamics (MD) simulation followed by post-simulation analysis. Furthermore, to assess the importance of features involved in the strong binding affinity, molecular field-based similarity analysis was performed. Based on comparative molecular docking and simulation studies of the selected phytocompounds with SARS-CoV-2 RdRp revealed that EBDGp possesses a stronger binding affinity (−23.32 kcal/mol) and stability than other phytocompounds and reference compound, Remdesivir (−19.36 kcal/mol). Molecular field-based similarity profiling has supported our study in the validation of the importance of the presence of hydroxyl groups in EBDGp, involved in increasing its binding affinity toward SARS-CoV-2 RdRp. Molecular docking and dynamic simulation results confirmed that EBDGp has better inhibitory potential than Remdesivir and can be an effective novel drug for SARS-CoV-2 RdRp. Furthermore, binding free energy calculations confirmed the higher stability of the SARS-CoV-2 RdRp-EBDGp complex. These results suggest that the EBDGp compound may emerge as a promising drug against SARS-CoV-2 and hence requires further experimental validation.

Binding Free Energy Calculations of Nine FDA-approved Protease Inhibitors Against HIV-1 Subtype C I36T↑T Containing 100 Amino Acids Per Monomer

2016 ◽  
Vol 87 (4) ◽  
pp. 487-498 ◽  
Author(s):  
Husain A. Lockhat ◽  
José R. A. Silva ◽  
Cláudio N. Alves ◽  
Thavendran Govender ◽  
Jerônimo Lameira ◽  
...  
Keyword(s):  
Amino Acids ◽  
Free Energy ◽  
Protease Inhibitors ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Subtype C ◽  
Energy Calculations ◽  
Binding Free Energy Calculations ◽  
Hiv 1

scholarly journals In silico exploration of phytoconstituents from Phyllanthus emblica and Aegle marmelos as potential therapeutics against SARS-CoV-2 RdRp

2021 ◽  
Author(s):  
Khushboo Pandey ◽  
Kiran Bharat Lokhande ◽  
K. venkateswara Swamy ◽  
Shuchi Nagar ◽  
Manjusha Dake
Keyword(s):  
Molecular Docking ◽  
Binding Affinity ◽  
Simulation Analysis ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Molecular Field ◽  
Hydroxyl Groups ◽  
Phyllanthus Emblica ◽  
Inhibitory Potential ◽  
Novel Drug

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) worldwide has increased the importance of computational tools to design a drug or vaccine in reduced time with minimum risk. Earlier studies have emphasized the important role of RNA-dependent RNA polymerase (RdRp) in SARS-CoV-2 replication as a potential drug target. In our study, comprehensive computational approaches were applied to identify potential compounds targeting RdRp of SARS-CoV-2. To study the binding affinity and stability of the phytocompounds from Phyllanthus emblica and Aegel marmelos within the defined binding site of SARS-CoV-2 RdRp, they were subjected to molecular docking, 100ns molecular dynamics (MD) simulation followed by post-simulation analysis. Further, to assess the importance of features involved in the strong binding affinity, molecular field-based similarity analysis was performed. Based on comparative molecular docking and simulation studies of the selected phytocompounds with SARS-CoV-2 RdRp revealed that, EBDGp possess stronger binding affinity (-23.32 kcal/mol) and stability than other phytocompounds and reference compound, Remdesivir (-19.36 kcal/mol). Molecular field-based similarity profiling has supported our study in the validation of the importance of the presence of hydroxyl groups in EBDGp, involved in increasing its binding affinity towards SARS-CoV-2 RdRp. Molecular docking and dynamic simulation results confirmed that EBDGp has better inhibitory potential than Remdesivir and can be an effective novel drug for SARS-CoV-2 RdRp. Furthermore, binding free energy calculations confirmed the higher stability of the SARS-CoV-2 RdRp-EBDGp complex. These results suggest that the EBDGp compound may emerge as a promising drug against SARS-CoV-2 and hence requires further experimental validation.

scholarly journals In Silico Identification of Novel Aromatic Compounds as Potential HIV-1 Entry Inhibitors Mimicking Cellular Receptor CD4

Viruses ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 746 ◽  
Author(s):  
Alexander M. Andrianov ◽  
Grigory I. Nikolaev ◽  
Yuri V. Kornoushenko ◽  
Wei Xu ◽  
Shibo Jiang ◽  
...  
Keyword(s):  
Binding Affinity ◽  
In Silico ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Cellular Receptor ◽  
Dynamic Simulations ◽  
Entry Inhibitors ◽  
Fusion Inhibitors ◽  
Gp120 Protein ◽  
Hiv 1

Despite recent progress in the development of novel potent HIV-1 entry/fusion inhibitors, there are currently no licensed antiviral drugs based on inhibiting the critical interactions of the HIV-1 envelope gp120 protein with cellular receptor CD4. In this connection, studies on the design of new small-molecule compounds able to block the gp120-CD4 binding are still of great value. In this work, in silico design of drug-like compounds containing the moieties that make the ligand active towards gp120 was performed within the concept of click chemistry. Complexes of the designed molecules bound to gp120 were then generated by molecular docking and optimized using semiempirical quantum chemical method PM7. Finally, the binding affinity analysis of these ligand/gp120 complexes was performed by molecular dynamic simulations and binding free energy calculations. As a result, five top-ranking compounds that mimic the key interactions of CD4 with gp120 and show the high binding affinity were identified as the most promising CD4-mimemic candidates. Taken together, the data obtained suggest that these compounds may serve as promising scaffolds for the development of novel, highly potent and broad anti-HIV-1 therapeutics.

scholarly journals Binding mode and free energy prediction of fisetin/β-cyclodextrin inclusion complexes

2014 ◽  
Vol 10 ◽  
pp. 2789-2799 ◽  
Author(s):  
Bodee Nutho ◽  
Wasinee Khuntawee ◽  
Chompoonut Rungnim ◽  
Piamsook Pongsawasdi ◽  
Peter Wolschann ◽  
...  
Keyword(s):  
Free Energy ◽  
Molecular Docking ◽  
Phenyl Ring ◽  
Binding Free Energy ◽  
Md Simulations ◽  
Binding Mode ◽  
Free Energy Calculations ◽  
Energy Prediction ◽  
Theoretical Approaches ◽  
Preferential Binding

In the present study, our aim is to investigate the preferential binding mode and encapsulation of the flavonoid fisetin in the nano-pore of β-cyclodextrin (β-CD) at the molecular level using various theoretical approaches: molecular docking, molecular dynamics (MD) simulations and binding free energy calculations. The molecular docking suggested four possible fisetin orientations in the cavity through its chromone or phenyl ring with two different geometries of fisetin due to the rotatable bond between the two rings. From the multiple MD results, the phenyl ring of fisetin favours its inclusion into the β-CD cavity, whilst less binding or even unbinding preference was observed in the complexes where the larger chromone ring is located in the cavity. All MM- and QM-PBSA/GBSA free energy predictions supported the more stable fisetin/β-CD complex of the bound phenyl ring. Van der Waals interaction is the key force in forming the complexes. In addition, the quantum mechanics calculations with M06-2X/6-31G(d,p) clearly showed that both solvation effect and BSSE correction cannot be neglected for the energy determination of the chosen system.

scholarly journals DFT Calculation, Molecular Docking and Molecular Dynamics Simulation Study on Substituted Phenylacetamide and Benzohydrazide Derivatives

2021 ◽  
Author(s):  
Vidyasrilekha Yele ◽  
Dilep Kumar Sigalapalli ◽  
Srikanth Jupudi ◽  
Mohammed Afzal Azam
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Docking ◽  
Binding Affinity ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Dynamics Simulation ◽  
Molecular Surface ◽  
Basis Set ◽  
Nucleophilic Attack

Abstract The atomic and molecular properties of the title compounds were calculated by Jaguar using a basis set B3LYP/6-31G**++ with hybrid DFT in the gas phase, to determine the chemical reactivity. Analysis of Quantum chemical features such as HOMO and LUMO explained that the electronic charge transfer occurred within the system through conjugated paths of the selected compounds. The nucleophilic and electrophilic reactive sites are recognized from the molecular electrostatic potential plot. Electrophilic and nucleophilic attack-prone molecular sites were predicted by mapping ALIE and ALEA values to the molecular surface. The bond dissociation energy of the high active compound 15 (2-chloro-N-(2-(2-(2-(2-chlorobenzoyl)hydrazineyl)-2-oxoethoxy)phenyl)acetamide) was calculated to assess the probability of compounds autoxidation or degradation. Further, molecular docking, binding free energy calculations, and ADMET profile of the degradation products (DPs) of compound 15 was carried out to determine the binding affinity and toxicity profile of the formed DPs compared with the parent compound. A 150 ns molecular dynamics (MD) simulation was performed to evaluate the binding stability of the compound 15/4URL complex using Desmond. Binding free energy and binding affinity of the complex were computed for 100 trajectory frames using the MM-GBSA approach.

scholarly journals Enhancing Paraoxon Binding to Organophosphorus Hydrolase Active Site

2021 ◽  
Vol 22 (23) ◽  
pp. 12624
Author(s):  
Léa El Khoury ◽  
David L. Mobley ◽  
Dongmei Ye ◽  
Susan B. Rempe
Keyword(s):  
Binding Affinity ◽  
Active Site ◽  
Binding Free Energy ◽  
Hot Spot ◽  
Substrate Binding ◽  
Kinetic Studies ◽  
Md Simulations ◽  
Binding Mode ◽  
Free Energy Calculations ◽  
Organophosphorus Hydrolase

Organophosphorus hydrolase (OPH) is a metalloenzyme that can hydrolyze organophosphorus agents resulting in products that are generally of reduced toxicity. The best OPH substrate found to date is diethyl p-nitrophenyl phosphate (paraoxon). Most structural and kinetic studies assume that the binding orientation of paraoxon is identical to that of diethyl 4-methylbenzylphosphonate, which is the only substrate analog co-crystallized with OPH. In the current work, we used a combined docking and molecular dynamics (MD) approach to predict the likely binding mode of paraoxon. Then, we used the predicted binding mode to run MD simulations on the wild type (WT) OPH complexed with paraoxon, and OPH mutants complexed with paraoxon. Additionally, we identified three hot-spot residues (D253, H254, and I255) involved in the stability of the OPH active site. We then experimentally assayed single and double mutants involving these residues for paraoxon binding affinity. The binding free energy calculations and the experimental kinetics of the reactions between each OPH mutant and paraoxon show that mutated forms D253E, D253E-H254R, and D253E-I255G exhibit enhanced substrate binding affinity over WT OPH. Interestingly, our experimental results show that the substrate binding affinity of the double mutant D253E-H254R increased by 19-fold compared to WT OPH.

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