Unveiling the Effect of Low pH on the SARS-CoV-2 Main Protease by Molecular Dynamics Simulations

(1) Background: Main Protease (Mpro) is an attractive therapeutic target that acts in the replication and transcription of the SARS-CoV-2 coronavirus. Mpro is rich in residues exposed to protonation/deprotonation changes which could affect its enzymatic function. This work aimed to explore the effect of the protonation/deprotonation states of Mpro at different pHs using computational techniques. (2) Methods: The different distribution charges were obtained in all the evaluated pHs by the Semi-Grand Canonical Monte Carlo (SGCMC) method. A set of Molecular Dynamics (MD) simulations was performed to consider the different protonation/deprotonation during 250 ns, verifying the structural stability of Mpro at different pHs. (3) Results: The present findings demonstrate that active site residues and residues that allow Mpro dimerisation was not affected by pH changes. However, Mpro substrate-binding residues were altered at low pHs, allowing the increased pocket volume. Additionally, the results of the solvent distribution around Sγ, Hγ, Nδ1 and Hδ1 atoms of the catalytic residues Cys145 and His41 showed a low and high-water affinity at acidic pH, respectively. It which could be crucial in the catalytic mechanism of SARS-CoV-2 Mpro at low pHs. Moreover, we analysed the docking interactions of PF-00835231 from Pfizer in the preclinical phase, which shows excellent affinity with the Mpro at different pHs. (4) Conclusion: Overall, these findings indicate that SARS-CoV-2 Mpro is highly stable at acidic pH conditions, and this inhibitor could have a desirable function at this condition.

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High-resolution mining of the SARS-CoV-2 main protease conformational space: supercomputer-driven unsupervised adaptive sampling

Chemical Science ◽

10.1039/d1sc00145k ◽

2021 ◽

Author(s):

Théo Jaffrelot Inizan ◽

Frédéric Célerse ◽

Olivier Adjoua ◽

Dina El Ahdab ◽

Luc-Henri Jolly ◽

...

Keyword(s):

Molecular Dynamics ◽

High Resolution ◽

Adaptive Sampling ◽

Force Fields ◽

Sampling Strategy ◽

Md Simulations ◽

Conformational Space ◽

Many Body ◽

Polarizable Force Fields ◽

Main Protease

We provide an unsupervised adaptive sampling strategy capable of producing μs-timescale molecular dynamics (MD) simulations of large biosystems using many-body polarizable force fields (PFFs).

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A Possible Mechanism of Graphene Oxide to Enhance Thermostability of D-Psicose 3-Epimerase Revealed by Molecular Dynamics Simulations

International Journal of Molecular Sciences ◽

10.3390/ijms221910813 ◽

2021 ◽

Vol 22 (19) ◽

pp. 10813

Author(s):

Congcong Li ◽

Zhongkui Lu ◽

Min Wang ◽

Siao Chen ◽

Lu Han ◽

...

Keyword(s):

Molecular Dynamics ◽

Thermal Stability ◽

Graphene Oxide ◽

Md Simulations ◽

Strong Interactions ◽

Limiting Factor ◽

Active Site Residues ◽

Detailed Mechanism ◽

Dynamics Simulations ◽

Thermal Stability Of

Thermal stability is a limiting factor for effective application of D-psicose 3-epimerase (DPEase) enzyme. Recently, it was reported that the thermal stability of DPEase was improved by immobilizing enzymes on graphene oxide (GO) nanoparticles. However, the detailed mechanism is not known. In this study, we investigated interaction details between GO and DPEase by performing molecular dynamics (MD) simulations. The results indicated that the domain (K248 to D268) of DPEase was an important anchor for immobilizing DPEase on GO surface. Moreover, the strong interactions between DPEase and GO can prevent loop α1′-α1 and β4-α4 of DPEase from the drastic fluctuation. Since these two loops contained active site residues, the geometry of the active pocket of the enzyme remained stable at high temperature after the DPEase was immobilized by GO, which facilitated efficient catalytic activity of the enzyme. Our research provided a detailed mechanism for the interaction between GO and DPEase at the nano–biology interface.

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Computational Studies of SARS-CoV-2 3CLpro: Insights from MD Simulations

International Journal of Molecular Sciences ◽

10.3390/ijms21155346 ◽

2020 ◽

Vol 21 (15) ◽

pp. 5346 ◽

Cited By ~ 5

Author(s):

Alessandro Grottesi ◽

Neva Bešker ◽

Andrew Emerson ◽

Candida Manelfi ◽

Andrea R. Beccari ◽

...

Keyword(s):

Conformational Dynamics ◽

Md Simulations ◽

Health Impact ◽

Respiratory Syndrome Virus ◽

Enzymatic Function ◽

Main Protease ◽

Loop Regions ◽

Dimeric Form ◽

And Function ◽

Shed Light

Given the enormous social and health impact of the pandemic triggered by severe acute respiratory syndrome 2 (SARS-CoV-2), the scientific community made a huge effort to provide an immediate response to the challenges posed by Coronavirus disease 2019 (COVID-19). One of the most important proteins of the virus is an enzyme, called 3CLpro or main protease, already identified as an important pharmacological target also in SARS and Middle East respiratory syndrome virus (MERS) viruses. This protein triggers the production of a whole series of enzymes necessary for the virus to carry out its replicating and infectious activities. Therefore, it is crucial to gain a deeper understanding of 3CLpro structure and function in order to effectively target this enzyme. All-atoms molecular dynamics (MD) simulations were performed to examine the different conformational behaviors of the monomeric and dimeric form of SARS-CoV-2 3CLpro apo structure, as revealed by microsecond time scale MD simulations. Our results also shed light on the conformational dynamics of the loop regions at the entry of the catalytic site. Studying, at atomic level, the characteristics of the active site and obtaining information on how the protein can interact with its substrates will allow the design of molecules able to block the enzymatic function crucial for the virus.

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Molecular docking and molecular dynamics simulations of fumarate hydratase and its mutant H235N complexed with pyromellitic acid and citrate

Journal of Bioinformatics and Computational Biology ◽

10.1142/s0219720017500263 ◽

2017 ◽

Vol 15 (06) ◽

pp. 1750026 ◽

Cited By ~ 1

Author(s):

S. Subasri ◽

Santosh Kumar Chaudhary ◽

K. Sekar ◽

Manish Kesherwani ◽

D. Velmurugan

Keyword(s):

Molecular Dynamics ◽

Active Site ◽

Model Building ◽

Hydrophobic Interactions ◽

Conformational Stability ◽

Fumarate Hydratase ◽

Md Simulations ◽

Major Effect ◽

Active Site Residues ◽

Pyromellitic Acid

Fumarase catalyzes the reversible, stereospecific hydration/dehydration of fumarate to L-malate during the Kreb’s cycle. In the crystal structure of the tetrameric fumarase, it was found that some of the active site residues S145, T147, N188 G364 and H235 had water-mediated hydrogen bonding interactions with pyromellitic acid and citrate which help to the protonation state for the conversion of fumarate to malate. When His 235 is mutated with Asn (H235N), water-mediated interactions were lost due to the shifting of active site water molecule by 0.7 Å away. Molecular dynamics (MD) simulations were also carried out by NAMD and analyzed using Assisted Model Building with Energy Refinement (AMBER) program to better understand the conformational stability and other aspects during the binding of pyromellitic acid and citrate with native and mutant FH. The role of hydrogen bonds and hydrophobic interactions was also analyzed. The present study confirms that the H235N mutation has a major effect on the catalytic activity of fumarase which is evident from the biochemical studies.

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Computer-based techniques for lead identification and optimization I: Basics

Physical Sciences Reviews ◽

10.1515/psr-2018-0113 ◽

2019 ◽

Vol 4 (6) ◽

Cited By ~ 5

Author(s):

Annalisa Maruca ◽

Francesca Alessandra Ambrosio ◽

Antonio Lupia ◽

Isabella Romeo ◽

Roberta Rocca ◽

...

Keyword(s):

Molecular Dynamics ◽

Md Simulations ◽

Lead Optimization ◽

Computational Techniques ◽

Starting Point ◽

Lead Identification ◽

Modeling Techniques ◽

Computer Based ◽

Identification Processes ◽

Telomeric Rna

Abstract This chapter focuses on computational techniques for identifying and optimizing lead molecules, with a special emphasis on natural compounds. A number of case studies have been specifically discussed, such as the case of the naphthyridine scaffold, discovered through a structure-based virtual screening (SBVS) and proposed as the starting point for further lead optimization process, to enhance its telomeric RNA selectivity. Another example is the case of Liphagal, a tetracyclic meroterpenoid extracted from Aka coralliphaga, known as PI3Kα inhibitor, provide an evidence for the design of new active congeners against PI3Kα using molecular dynamics (MD) simulations. These are only two of the numerous examples of the computational techniques’ powerful in drug design and drug discovery fields. Finally, the design of drugs that can simultaneously interact with multiple targets as a promising approach for treating complicated diseases has been reported. An example of polypharmacological agents are the compounds extracted from mushrooms identified by means of molecular docking experiments. This chapter may be a useful manual of molecular modeling techniques used in the lead-optimization and lead identification processes.

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Putative Inhibitors of SARS-CoV-2 Main Protease from A Library of Marine Natural Products: A Virtual Screening and Molecular Modeling Study

Marine Drugs ◽

10.3390/md18040225 ◽

2020 ◽

Vol 18 (4) ◽

pp. 225 ◽

Cited By ~ 56

Author(s):

Davide Gentile ◽

Vincenzo Patamia ◽

Angela Scala ◽

Maria Teresa Sciortino ◽

Anna Piperno ◽

...

Keyword(s):

Molecular Dynamics ◽

Severe Acute Respiratory Syndrome ◽

Middle Eastern ◽

Pharmacophore Model ◽

Hiv Protease ◽

Marine Natural Product ◽

Computational Techniques ◽

Hiv Protease Inhibitors ◽

Global Public Health ◽

Main Protease

The current emergency due to the worldwide spread of the COVID-19 caused by the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a great concern for global public health. Already in the past, the outbreak of severe acute respiratory syndrome (SARS) in 2003 and Middle Eastern respiratory syndrome (MERS) in 2012 demonstrates the potential of coronaviruses to cross-species borders and further underlines the importance of identifying new-targeted drugs. An ideal antiviral agent should target essential proteins involved in the lifecycle of SARS-CoV. Currently, some HIV protease inhibitors (i.e., Lopinavir) are proposed for the treatment of COVID-19, although their effectiveness has not yet been assessed. The main protease (Mpro) provides a highly validated pharmacological target for the discovery and design of inhibitors. We identified potent Mpro inhibitors employing computational techniques that entail the screening of a Marine Natural Product (MNP) library. MNP library was screened by a hyphenated pharmacophore model, and molecular docking approaches. Molecular dynamics and re-docking further confirmed the results obtained by structure-based techniques and allowed this study to highlight some crucial aspects. Seventeen potential SARS-CoV-2 Mpro inhibitors have been identified among the natural substances of marine origin. As these compounds were extensively validated by a consensus approach and by molecular dynamics, the likelihood that at least one of these compounds could be bioactive is excellent.

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Inhibitors of SARS-CoV-2 Main Protease from a Library of Marine Natural Products: A Virtual Screening and Molecular Modeling Study

10.20944/preprints202003.0372.v1 ◽

2020 ◽

Cited By ~ 2

Author(s):

Davide Gentile ◽

Vincenzo Patamia ◽

Angela Scala ◽

Maria Teresa Sciortino ◽

Anna Piperno ◽

...

Keyword(s):

Molecular Dynamics ◽

Middle Eastern ◽

Pharmacophore Model ◽

Antiviral Agent ◽

Hiv Protease ◽

Marine Natural Product ◽

Computational Techniques ◽

Hiv Protease Inhibitors ◽

Global Public Health ◽

Main Protease

The current emergency due to the worldwide spread of the COVID-19 caused by the new SARS-CoV-2 is a great concern for global public health. Already in the past, the outbreak of severe acute respiratory syndrome (SARS) in 2003 and Middle Eastern respiratory syndrome (MERS) in 2012 demonstrates the potential of coronaviruses to cross-species borders and further underlines the importance of identifying new-targeted drugs. An ideal antiviral agent should target essential proteins involved in the lifecycle of SARS-CoV. Currently, some HIV protease inhibitors (i.e., Lopinavir) are proposed for the treatment of COVID-19, although their effectiveness was not yet assessed. The main protease (Mpro) provides a highly validated pharmacological target for the discovery and design of inhibitors. We identified potent Mpro inhibitors employing computational techniques that entail the screening of a Marine Natural Product (MNP) library. MNP library was screened by hyphenated pharmacophore model, and molecular docking approaches. Molecular dynamics and re-docking further confirmed the results obtained by structure-based techniques and allowed to highlight some crucial aspects. Seventeen potential SARS-CoV-2 Mpro inhibitors have been identified among the natural substances of marine origin. As these compounds were extensively validated by a consensus approach and by molecular dynamics, the likelihood that at least one of these compounds could be bioactive is excellent.

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Targeting Allosteric Pockets of SARS-CoV-2 Main Protease Mpro

10.26434/chemrxiv.12857927.v2 ◽

2020 ◽

Author(s):

Zahoor Ahmad Bhat ◽

Dheeraj Chitara ◽

Jawed Iqbal1 ◽

Sanjeev. B.S. ◽

Arumugam Madhumalar

Keyword(s):

Molecular Dynamics ◽

Combination Therapy ◽

Viral Replication ◽

Drug Target ◽

Drug Testing ◽

Therapeutic Option ◽

Md Simulations ◽

Main Protease ◽

Experimental Drug ◽

Conformational Plasticity

<h3>Repurposing of antivirals is an attractive therapeutic option for the treatment of COVID-19. Mpro (also called 3CLpro) is a key protease of SARS-CoV-2 involved in viral replication, and is a promising drug target for testing the existing antivirals. A major challenge to test the efficacy of antivirals is the conformational plasticity of Mpro and its future mutation prone flexibility. To address this, we hereby propose combination therapy by drugging two specific additional pockets of Mpro probed in our studies. Long scale Molecular Dynamics (MD) simulations provide evidence of these additional sites being allosteric. Suitable choice of drugs in catalytic and allosteric pockets appear to be essential for combination therapy. Current study, based on docking and extensive set of MD simulations, finds the combination of Elbasvir, Glecaprevir, Ritonavir to be a viable candidate for further experimental drug testing/pharmacophore design for Mpro. </h3>

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Targeting Allosteric Pockets of SARS-CoV-2 Main Protease Mpro

10.26434/chemrxiv.12857927 ◽

2020 ◽

Author(s):

Zahoor Ahmad Bhat ◽

Dheeraj Chitara ◽

Jawed Iqbal1 ◽

Sanjeev. B.S. ◽

Arumugam Madhumalar

Keyword(s):

Molecular Dynamics ◽

Combination Therapy ◽

Viral Replication ◽

Drug Target ◽

Drug Testing ◽

Therapeutic Option ◽

Md Simulations ◽

Main Protease ◽

Experimental Drug ◽

Conformational Plasticity

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Structural and functional roles of dynamically correlated residues in thymidylate kinase

Acta Crystallographica Section D Structural Biology ◽

10.1107/s2059798318002267 ◽

2018 ◽

Vol 74 (4) ◽

pp. 341-354 ◽

Cited By ~ 2

Author(s):

Santosh Kumar Chaudhary ◽

Jeyaraman Jeyakanthan ◽

Kanagaraj Sekar

Keyword(s):

Molecular Dynamics ◽

Conformational Changes ◽

Active Site ◽

Bound States ◽

Catalytic Mechanism ◽

Phosphoryl Transfer ◽

Active Site Residues ◽

Thymidylate Kinase ◽

Binary And Ternary Complexes ◽

Insight Into

Thymidylate kinase is an important enzyme in DNA synthesis. It catalyzes the conversion of thymidine monophosphate to thymidine diphosphate, with ATP as the preferred phosphoryl donor, in the presence of Mg2+. In this study, the dynamics of the active site and the communication paths between the substrates, ATP and TMP, are reported for thymidylate kinase fromThermus thermophilus. Conformational changes upon ligand binding and the path for communication between the substrates and the protein are important in understanding the catalytic mechanism of the enzyme. High-resolution X-ray crystal structures of thymidylate kinase in apo and ligand-bound states were solved. This is the first report of structures of binary and ternary complexes of thymidylate kinase with its natural substrates ATP and ATP–TMP, respectively. Distinct conformations of the active-site residues, the P-loop and the LID region observed in the apo and ligand-bound structures revealed that their concerted motion is required for the binding and proper positioning of the substrate TMP. Structural analyses provide an insight into the mode of substrate binding at the active site. The residues involved in communication between the substrates were identified through network analysis using molecular-dynamics simulations. The residues identified showed high sequence conservation across species. Biochemical analyses show that mutations of these residues either resulted in a loss of activity or affected the thermal stability of the protein. Further, molecular-dynamics analyses of mutants suggest that the proper positioning of TMP is important for catalysis. These data also provide an insight into the phosphoryl-transfer mechanism.

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