scholarly journals Identification of promising drug candidates against Non-Structural Protein 15 (NSP15) from SARS-CoV-2: an in silico assisted drug-repurposing studies

2020 ◽  
Author(s):  
Rameez Jabeer Khan ◽  
Rajat Kumar Jha ◽  
Ekampreet Singh ◽  
Monika Jain ◽  
Gizachew Muluneh Amera ◽  
...  
Keyword(s):  
Free Energy ◽  
In Silico ◽  
Binding Free Energy ◽  
Drug Repurposing ◽  
Md Simulations ◽  
Therapeutic Agents ◽  
Global Dynamics ◽  
Host Immune System ◽  
Structural Protein ◽  
Drug Candidates

<div>The recent COVID-19 pandemic caused by SARS-CoV-2 has recorded a high number of infected people across the globe. The notorious nature of the virus makes it necessary for us to identify promising therapeutic agents in a time-sensitive manner. The current study utilises an <i>in silico</i> based drug repurposing approach to identify potential drug candidates targeting non-structural protein 15 (NSP15), i.e. a uridylate specific endoribonuclease of SARS-CoV-2</div><div>which plays an indispensable role in RNA processing and viral immune evasion from the host immune system. NSP15 was screened against an in-house library of 123 antiviral drugs obtained from the DrugBank database from which three promising drug candidates were identified based on their estimated free energy of binding (<i>ΔG</i>), estimated inhibition constant (<i>Ki</i>), the orientation of drug molecules in the active site and the key interacting residues of</div><div>NSP15. The MD simulations were performed for the selected NSP15-drug complexes along with free protein to mimic on their physiological state. The binding free energies of the selected NSP15-drug complexes were also calculated using the trajectories of MD simulations of NSP15-drug complexes through MM/PBSA (Molecular Mechanics with Poisson-Boltzmann and surface area solvation) approach where NSP15-Simeprevir (-242.559 kJ/mol) and NSP15-Paritaprevir (-149.557 kJ/mol) exhibited the strongest binding affinities. Together with the results of molecular docking, global dynamics, essential dynamics and binding free energy analysis, we propose that Simeprevir and Paritaprevir are promising drug candidates for the inhibition of NSP15 and could act as potential therapeutic agents against SARS-CoV-2.</div>

scholarly journals Identification of promising drug candidates against Non-Structural Protein 15 (NSP15) from SARS-CoV-2: an in silico assisted drug-repurposing studies

2020 ◽  
Author(s):  
Rameez Jabeer Khan ◽  
Rajat Kumar Jha ◽  
Ekampreet Singh ◽  
Monika Jain ◽  
Gizachew Muluneh Amera ◽  
...  
Keyword(s):  
Free Energy ◽  
In Silico ◽  
Binding Free Energy ◽  
Drug Repurposing ◽  
Md Simulations ◽  
Therapeutic Agents ◽  
Global Dynamics ◽  
Host Immune System ◽  
Structural Protein ◽  
Drug Candidates

<div>The recent COVID-19 pandemic caused by SARS-CoV-2 has recorded a high number of infected people across the globe. The notorious nature of the virus makes it necessary for us to identify promising therapeutic agents in a time-sensitive manner. The current study utilises an <i>in silico</i> based drug repurposing approach to identify potential drug candidates targeting non-structural protein 15 (NSP15), i.e. a uridylate specific endoribonuclease of SARS-CoV-2</div><div>which plays an indispensable role in RNA processing and viral immune evasion from the host immune system. NSP15 was screened against an in-house library of 123 antiviral drugs obtained from the DrugBank database from which three promising drug candidates were identified based on their estimated free energy of binding (<i>ΔG</i>), estimated inhibition constant (<i>Ki</i>), the orientation of drug molecules in the active site and the key interacting residues of</div><div>NSP15. The MD simulations were performed for the selected NSP15-drug complexes along with free protein to mimic on their physiological state. The binding free energies of the selected NSP15-drug complexes were also calculated using the trajectories of MD simulations of NSP15-drug complexes through MM/PBSA (Molecular Mechanics with Poisson-Boltzmann and surface area solvation) approach where NSP15-Simeprevir (-242.559 kJ/mol) and NSP15-Paritaprevir (-149.557 kJ/mol) exhibited the strongest binding affinities. Together with the results of molecular docking, global dynamics, essential dynamics and binding free energy analysis, we propose that Simeprevir and Paritaprevir are promising drug candidates for the inhibition of NSP15 and could act as potential therapeutic agents against SARS-CoV-2.</div>

scholarly journals Possibility of HIV-1 Protease Inhibitors-Clinical Trial Drugs as Repurposed Drugs for SARSCoV-2 Main Protease: A Molecular Docking, Molecular Dynamics and Binding Free Energy Simulation Study

2020 ◽  
Author(s):  
Ancy Iruthayaraj ◽  
Sivanandam Magudeeswaran ◽  
Kumaradhas Poomani
Keyword(s):  
Clinical Trial ◽  
Amino Acids ◽  
Free Energy ◽  
Binding Free Energy ◽  
Drug Repurposing ◽  
Md Simulations ◽  
Binding Mechanism ◽  
Main Protease ◽  
Repurposed Drugs ◽  
Hiv 1

<p>Initially, the SARS-CoV-2 virus was emerged from Wuhan, China and rapidly spreading across the world and urges the scientific community to develop antiviral therapeutic agents. Among several strategies, drug repurposing will help to react immediately to overcome COVID-19 pandemic. In the present study, we have chosen two clinical trial drugs TMB607 and TMC310911 are the inhibitors of HIV-1 protease to use as the inhibitors of SARS-CoV-2 main protease (M<sup>pro</sup>) enzyme. To make use of these two inhibitors as the repurposed drugs for COVID-19, it is essential to know the molecular basis of binding mechanism of these two molecules with the SARS-CoV-2 main protease (M<sup>pro</sup>). Understand the binding mechanism; we performed the molecular docking, molecular dynamics (MD) simulations and binding free energy calculations against the SARS-CoV-2 M<sup>pro</sup>. The docking results indicate that both molecules form intermolecular interactions with the active site amino acids of M<sup>pro</sup> enzyme. However, during the MD simulations, TMB607 forms strong interactions with the key amino acids of M<sup>pro</sup> and remains intact. The RMSD and RMSF values of both complexes were stable throughout the MD simulations. The MM-GBSA binding free energy values of both complexes are -43.7 and -34.9 kcal/mol, respectively. This <i>in silico</i> study proves that the TMB607 molecule binds strongly with the SARS-CoV-2 M<sup>pro</sup> enzyme and it is suitable for the drug repurposing of COVID-19 and further drug designing.</p>

scholarly journals Possibility of HIV-1 Protease Inhibitors-Clinical Trial Drugs as Repurposed Drugs for SARSCoV-2 Main Protease: A Molecular Docking, Molecular Dynamics and Binding Free Energy Simulation Study

2020 ◽  
Author(s):  
Ancy Iruthayaraj ◽  
Sivanandam Magudeeswaran ◽  
Kumaradhas Poomani
Keyword(s):  
Clinical Trial ◽  
Amino Acids ◽  
Free Energy ◽  
Binding Free Energy ◽  
Drug Repurposing ◽  
Md Simulations ◽  
Binding Mechanism ◽  
Main Protease ◽  
Repurposed Drugs ◽  
Hiv 1

<p>Initially, the SARS-CoV-2 virus was emerged from Wuhan, China and rapidly spreading across the world and urges the scientific community to develop antiviral therapeutic agents. Among several strategies, drug repurposing will help to react immediately to overcome COVID-19 pandemic. In the present study, we have chosen two clinical trial drugs TMB607 and TMC310911 are the inhibitors of HIV-1 protease to use as the inhibitors of SARS-CoV-2 main protease (M<sup>pro</sup>) enzyme. To make use of these two inhibitors as the repurposed drugs for COVID-19, it is essential to know the molecular basis of binding mechanism of these two molecules with the SARS-CoV-2 main protease (M<sup>pro</sup>). Understand the binding mechanism; we performed the molecular docking, molecular dynamics (MD) simulations and binding free energy calculations against the SARS-CoV-2 M<sup>pro</sup>. The docking results indicate that both molecules form intermolecular interactions with the active site amino acids of M<sup>pro</sup> enzyme. However, during the MD simulations, TMB607 forms strong interactions with the key amino acids of M<sup>pro</sup> and remains intact. The RMSD and RMSF values of both complexes were stable throughout the MD simulations. The MM-GBSA binding free energy values of both complexes are -43.7 and -34.9 kcal/mol, respectively. This <i>in silico</i> study proves that the TMB607 molecule binds strongly with the SARS-CoV-2 M<sup>pro</sup> enzyme and it is suitable for the drug repurposing of COVID-19 and further drug designing.</p>

scholarly journals Automation of absolute protein-ligand binding free energy calculations for docking refinement and compound evaluation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Germano Heinzelmann ◽  
Michael K. Gilson
Keyword(s):  
Free Energy ◽  
Early Stage ◽  
Binding Free Energy ◽  
Low Cost ◽  
Free Energy Calculations ◽  
Free Energies ◽  
Energy Calculations ◽  
Drug Candidates ◽  
Binding Free Energy Calculations ◽  
Binding Free Energies

AbstractAbsolute binding free energy calculations with explicit solvent molecular simulations can provide estimates of protein-ligand affinities, and thus reduce the time and costs needed to find new drug candidates. However, these calculations can be complex to implement and perform. Here, we introduce the software BAT.py, a Python tool that invokes the AMBER simulation package to automate the calculation of binding free energies for a protein with a series of ligands. The software supports the attach-pull-release (APR) and double decoupling (DD) binding free energy methods, as well as the simultaneous decoupling-recoupling (SDR) method, a variant of double decoupling that avoids numerical artifacts associated with charged ligands. We report encouraging initial test applications of this software both to re-rank docked poses and to estimate overall binding free energies. We also show that it is practical to carry out these calculations cheaply by using graphical processing units in common machines that can be built for this purpose. The combination of automation and low cost positions this procedure to be applied in a relatively high-throughput mode and thus stands to enable new applications in early-stage drug discovery.

scholarly journals Structural and Energetic Affinity of Annocatacin B with ND1 Subunit of the Human Mitochondrial Respiratory Complex I as a Potential Inhibitor: An In Silico Comparison Study with the Known Inhibitor Rotenone

Polymers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 1840
Author(s):  
Camilo Febres-Molina ◽  
Jorge A. Aguilar-Pineda ◽  
Pamela L. Gamero-Begazo ◽  
Haruna L. Barazorda-Ccahuana ◽  
Diego E. Valencia ◽  
...  
Keyword(s):  
Free Energy ◽  
In Silico ◽  
Complex I ◽  
Binding Free Energy ◽  
Biological Activities ◽  
Experimental Studies ◽  
Respiratory Complex ◽  
Mitochondrial Respiratory Complex ◽  
Respiratory Complex I ◽  
Mitochondrial Respiratory

ND1 subunit possesses the majority of the inhibitor binding domain of the human mitochondrial respiratory complex I. This is an attractive target for the search for new inhibitors that seek mitochondrial dysfunction. It is known, from in vitro experiments, that some metabolites from Annona muricata called acetogenins have important biological activities, such as anticancer, antiparasitic, and insecticide. Previous studies propose an inhibitory activity of bovine mitochondrial respiratory complex I by bis-tetrahydrofurans acetogenins such as annocatacin B, however, there are few studies on its inhibitory effect on human mitochondrial respiratory complex I. In this work, we evaluate the in silico molecular and energetic affinity of the annocatacin B molecule with the human ND1 subunit in order to elucidate its potential capacity to be a good inhibitor of this subunit. For this purpose, quantum mechanical optimizations, molecular dynamics simulations and the molecular mechanics/Poisson–Boltzmann surface area (MM/PBSA) analysis were performed. As a control to compare our outcomes, the molecule rotenone, which is a known mitochondrial respiratory complex I inhibitor, was chosen. Our results show that annocatacin B has a greater affinity for the ND1 structure, its size and folding were probably the main characteristics that contributed to stabilize the molecular complex. Furthermore, the MM/PBSA calculations showed a 35% stronger binding free energy compared to the rotenone complex. Detailed analysis of the binding free energy shows that the aliphatic chains of annocatacin B play a key role in molecular coupling by distributing favorable interactions throughout the major part of the ND1 structure. These results are consistent with experimental studies that mention that acetogenins may be good inhibitors of the mitochondrial respiratory complex I.

scholarly journals Solvents to Fragments to Drugs: MD Applications in Drug Design

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3269 ◽  
Author(s):  
Lucas Defelipe ◽  
Juan Arcon ◽  
Carlos Modenutti ◽  
Marcelo Marti ◽  
Adrián Turjanski ◽  
...  
Keyword(s):  
Binding Free Energy ◽  
Mixed Solvents ◽  
Md Simulations ◽  
Binding Mode ◽  
Condensed State ◽  
Protein Targets ◽  
Drug Candidates ◽  
Interaction Sites ◽  
Aqueous Solvation ◽  
The Common

Simulations of molecular dynamics (MD) are playing an increasingly important role in structure-based drug discovery (SBDD). Here we review the use of MD for proteins in aqueous solvation, organic/aqueous mixed solvents (MDmix) and with small ligands, to the classic SBDD problems: Binding mode and binding free energy predictions. The simulation of proteins in their condensed state reveals solvent structures and preferential interaction sites (hot spots) on the protein surface. The information provided by water and its cosolvents can be used very effectively to understand protein ligand recognition and to improve the predictive capability of well-established methods such as molecular docking. The application of MD simulations to the study of the association of proteins with drug-like compounds is currently only possible for specific cases, as it remains computationally very expensive and labor intensive. MDmix simulations on the other hand, can be used systematically to address some of the common tasks in SBDD. With the advent of new tools and faster computers we expect to see an increase in the application of mixed solvent MD simulations to a plethora of protein targets to identify new drug candidates.

Estimation of the ligand-binding free energy of checkpoint kinase 1 via non-equilibrium MD simulations

2020 ◽  
Vol 100 ◽  
pp. 107648 ◽  
Author(s):  
Nguyen Thi Mai ◽  
Ngo Thi Lan ◽  
Thien Y Vu ◽  
Phuong Thi Mai Duong ◽  
Nguyen Thanh Tung ◽  
...  
Keyword(s):  
Free Energy ◽  
Ligand Binding ◽  
Binding Free Energy ◽  
Md Simulations ◽  
Checkpoint Kinase ◽  
Checkpoint Kinase 1 ◽  
Non Equilibrium

scholarly journals Three Alkaloids from an Apocynaceae Species, Aspidosperma spruceanum as Antileishmaniasis Agents by In Silico Demo-case Studies

Plants ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 983 ◽  
Author(s):  
Diana Morales-Jadán ◽  
José Blanco-Salas ◽  
Trinidad Ruiz-Téllez ◽  
Francisco Centeno
Keyword(s):  
Free Energy ◽  
Active Site ◽  
In Silico ◽  
Binding Free Energy ◽  
New Drugs ◽  
Neglected Tropical Disease ◽  
Physiological Importance ◽  
Promising Tool ◽  
Binding Pockets ◽  
Simulation Results

This paper is focused on demonstrating with a real case that Ethnobotany added to Bioinformatics is a promising tool for new drugs search. It encourages the in silico investigation of “challua kaspi”, a medicinal kichwa Amazonian plant (Aspidosperma spruceanum) against a Neglected Tropical Disease, leishmaniasis. The illness affects over 150 million people especially in subtropical regions, there is no vaccination and conventional treatments are unsatisfactory. In attempts to find potent and safe inhibitors of its etiological agent, Leishmania, we recovered the published traditional knowledge on kichwa antimalarials and selected three A. spruceanum alkaloids, (aspidoalbine, aspidocarpine and tubotaiwine), to evaluate by molecular docking their activity upon five Leishmania targets: DHFR-TS, PTR1, PK, HGPRT and SQS enzymes. Our simulation results suggest that aspidoalbine interacts competitively with the five targets, with a greater affinity for the active site of PTR1 than some physiological ligands. Our virtual data also point to the demonstration of few side effects. The predicted binding free energy has a greater affinity to Leishmania proteins than to their homologous in humans (TS, DHR, PKLR, HGPRT and SQS), and there is no match with binding pockets of physiological importance. Keys for the in silico protocols applied are included in order to offer a standardized method replicable in other cases. Apocynaceae having ethnobotanical use can be virtually tested as molecular antileishmaniasis new drugs.

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