scholarly journals Remdesivir Strongly Binds to RNA-Dependent RNA Polymerase, Membrane Protein, and Main Protease of SARS-CoV-2: Indication From Molecular Modeling and Simulations

2021 ◽  
Vol 12 ◽  
Author(s):  
Faez Iqbal Khan ◽  
Tongzhou Kang ◽  
Haider Ali ◽  
Dakun Lai
Keyword(s):  
Membrane Protein ◽  
Rna Polymerase ◽  
Broad Spectrum ◽  
Accessible Surface Area ◽  
New Drugs ◽  
Solvent Accessible Surface Area ◽  
Rna Dependent Rna Polymerase ◽  
Strong Binding ◽  
Main Protease ◽  
Accessible Surface

Development of new drugs is a time-taking and expensive process. Comprehensive efforts are being made globally toward the search of therapeutics against SARS-CoV-2. Several drugs such as remdesivir, favipiravir, ritonavir, and lopinavir have been included in the treatment regimen and shown effective results in several cases. Among the existing broad-spectrum antiviral drugs, remdesivir is found to be more effective against SARS-CoV-2. Remdesivir has broad-spectrum antiviral action against many single-stranded RNA viruses including pathogenic SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). In this study, we proposed that remdesivir strongly binds to membrane protein (Mprotein), RNA-dependent RNA polymerase (RDRP), and main protease (Mprotease) of SARS-CoV-2. It might show antiviral activity by inhibiting more than one target. It has been found that remdesivir binds to Mprotease, Mprotein, and RDRP with −7.8, −7.4, and −7.1 kcal/mol, respectively. The structure dynamics study suggested that binding of remdesivir leads to unfolding of RDRP. It has been found that strong binding of remdesivir to Mprotein leads to decrease in structural deviations and gyrations. Additionally, the average solvent-accessible surface area of Mprotein decreases from 127.17 to 112.12 nm2, respectively. Furthermore, the eigenvalues and the trace of the covariance matrix were found to be low in case of Mprotease–remdesivir, Mprotein–remdesivir, and RDRP–remdesivir. Binding of remdesivir to Mprotease, Mprotein, and RDRP reduces the average motions in protein due to its strong binding. The MMPBSA calculations also suggested that remdesivir has strong binding affinity with Mprotein, Mprotease, and RDRP. The detailed analysis suggested that remdesivir has more than one target of SARS-CoV-2.

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.

Application of the ESMACS Binding Free Energy Protocol to a Highly Varied Ligand Dataset: Lactate Dehydogenase A

2019 ◽  
Author(s):  
David Wright ◽  
Fouad Husseini ◽  
Shunzhou Wan ◽  
Christophe Meyer ◽  
Herman Van Vlijmen ◽  
...  
Keyword(s):  
Free Energy ◽  
Surface Area ◽  
Binding Free Energy ◽  
Normal Mode Analysis ◽  
Binding Mode ◽  
Accessible Surface Area ◽  
Solvent Accessible Surface Area ◽  
Mode Analysis ◽  
Energy Calculation ◽  
Accessible Surface

<div>Here, we evaluate the performance of our range of ensemble simulation based binding free energy calculation protocols, called ESMACS (enhanced sampling of molecular dynamics with approximation of continuum solvent) for use in fragment based drug design scenarios. ESMACS is designed to generate reproducible binding affinity predictions from the widely used molecular mechanics Poisson-Boltzmann surface area (MMPBSA) approach. We study ligands designed to target two binding pockets in the lactate dehydogenase A target protein, which vary in size, charge and binding mode. When comparing to experimental results, we obtain excellent statistical rankings across this highly diverse set of ligands. In addition, we investigate three approaches to account for entropic contributions not captured by standard MMPBSA calculations: (1) normal mode analysis, (2) weighted solvent accessible surface area (WSAS) and (3) variational entropy. </div>

scholarly journals PAMAM dendrimer: a pH-controlled nanosponge

2017 ◽  
Vol 95 (9) ◽  
pp. 991-998 ◽  
Author(s):  
Prabal K. Maiti
Keyword(s):  
Accessible Surface Area ◽  
Pamam Dendrimer ◽  
Low Ph ◽  
Dynamics Simulation ◽  
Solvent Accessible Surface Area ◽  
Water Molecules ◽  
Accessible Volume ◽  
Accessible Surface ◽  
Solvent Accessible Surface ◽  
Ph Controlled

Using fully atomistic molecular dynamics simulation that are several hundred nanoseconds long, we demonstrate the pH-controlled sponge action of PAMAM dendrimer. We show how at varying pH levels, the PAMAM dendrimer acts as a wet sponge; at neutral or low pH levels, the dendrimer expands noticeably and the interior of the dendrimer opens up to host several hundreds to thousands of water molecules depending on the generation number. Increasing the pH (i.e., going from low pH to high pH) leads to the collapse of the dendrimer size, thereby expelling the inner water, which mimics the ‘sponge’ action. As the dendrimer size swells up at a neutral pH or low pH due to the electrostatic repulsion between the primary and tertiary amines that are protonated at this pH, there is dramatic increase in the available solvent accessible surface area (SASA), as well as solvent accessible volume (SAV).

scholarly journals Mutations in RBD of SARS-CoV-2 Omicron variant result stronger binding to human ACE2 protein

2021 ◽  
Author(s):  
Cecylia Severin Lupala ◽  
Yongjin Ye ◽  
Hong Chen ◽  
Xiaodong Su ◽  
Haiguang Liu
Keyword(s):  
Complex Structure ◽  
Tight Binding ◽  
Accessible Surface Area ◽  
Solvent Accessible Surface Area ◽  
Original Strain ◽  
Receptor Binding Domain ◽  
Bonding Interaction ◽  
Accessible Surface ◽  
Dynamics Simulations ◽  
Solvent Accessible Surface

The spreading of SARS-CoV-2 virus resulted the COVID-19 pandemic, which has caused more than 5 millions of death globally. Several major variants of SARS-CoV-2 have emerged and placed challenges in controlling the infections. The recently emerged Omicron variant raised serious concerns about reducing efficacy of antibodies or vaccines, due to its vast mutations. We modelled the complex structure of human ACE2 protein and the receptor binding domain of Omicron variant, then conducted atomistic molecular dynamics simulations to study the binding interactions. The analysis shows that the Omicron variant RBD binds more strongly to the human ACE2 protein than the original strain. The mutation at the ACE2-RBD interface enhanced the tight binding by increasing hydrogen bonding interaction and enlarging buried solvent accessible surface area.

scholarly journals Analysis of Two-State Folding Using Parabolic Approximation I: Hypothesis

2016 ◽  
Author(s):  
Robert S Sade
Keyword(s):  
Gibbs Energy ◽  
Accessible Surface Area ◽  
Solvent Accessible Surface Area ◽  
Parabolic Approximation ◽  
Energy Functions ◽  
State Ensemble ◽  
The Mean ◽  
Accessible Surface ◽  
Transition State Ensemble ◽  
Solvent Accessible Surface

A model which treats the denatured and native conformers of spontaneously-folding fixed two-state systems as being confined to harmonic Gibbs energy-wells has been developed. Within the assumptions of this model the Gibbs energy functions of the denatured (DSE) and the native state (NSE) ensembles are described by parabolas, with the mean length of the reaction coordinate (RC) being given by the temperature-invariant denaturant m value. Consequently, the ensemble-averaged position of the transition state ensemble (TSE) along the RC, and the ensemble-averaged Gibbs energy of the TSE are determined by the intersection of the DSE and the NSE-parabolas. The equations derived enable equilibrium stability and the rate constants to be rationalized in terms of the mean and the variance of the Gaussian distribution of the solvent accessible surface area of the conformers in the DSE and the NSE. The implications of this model for protein folding are discussed.

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