Energy-optimized pharmacophore coupled virtual screening in the discovery of quorum sensing inhibitors of LasR protein of <i>Pseudomonas aeruginosa</i>

Nain, Zulkar; Syed, Shifath Bin; Karim, Mohammad Minnatul; Islam, Ariful; Adhikari, Utpal

doi:10.1080/07391102.2019.1700168

Cited by 22 publications

(12 citation statements)

References 83 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In our study, the stable nature of the docked complex was evident over a short period of time. The average RMSD value was in line with those of previous studies ( 110 , 111 ), in which several druglike small molecules achieved stability in a similar time frame ( 111 ). This stability originates from the different residues and interactions present in the side chain of the complex ( 112 ).…”

Section: Discussionsupporting

confidence: 90%

“…The fluctuation of the side chain was low, and only a small fluctuating region was identified, which could be due to the lack of contacts or flexible loops. Rigid structural conformations were revealed by measurements of the Rg during the simulation period ( 111 ). Superimpositions performed during the molecular dynamics simulation revealed that the post-molecular dynamics structures remained in the same cavity as the docked structure.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

A molecular modelling approach for identifying antiviral selenium-containing heterocyclic compounds that inhibit the main protease of SARS-CoV-2: an in silico investigation

Rakib¹,

Nain

Sami

et al. 2021

Briefings in Bioinformatics

Self Cite

View full text Add to dashboard Cite

Coronavirus disease 2019 (COVID-19), an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been declared a global pandemic by the World Health Organization, and the situation worsens daily, associated with acute increases in case fatality rates. The main protease (Mpro) enzyme produced by SARS-CoV-2 was recently demonstrated to be responsible for not only viral reproduction but also impeding host immune responses. The element selenium (Se) plays a vital role in immune functions, both directly and indirectly. Thus, we hypothesised that Se-containing heterocyclic compounds might curb the activity of SARS-CoV-2 Mpro. We performed a molecular docking analysis and found that several of the selected selenocompounds showed potential binding affinities for SARS-CoV-2 Mpro, especially ethaselen (49), which exhibited a docking score of −6.7 kcal/mol compared with the −6.5 kcal/mol score for GC376 (positive control). Drug-likeness calculations suggested that these compounds are biologically active and possess the characteristics of ideal drug candidates. Based on the binding affinity and drug-likeness results, we selected the 16 most effective selenocompounds as potential anti-COVID-19 drug candidates. We also validated the structural integrity and stability of the drug candidate through molecular dynamics simulation. Using further in vitro and in vivo experiments, we believe that the targeted compound identified in this study (ethaselen) could pave the way for the development of prospective drugs to combat SARS-CoV-2 infections and trigger specific host immune responses.

show abstract

Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

A molecular modelling approach for identifying antiviral selenium-containing heterocyclic compounds that inhibit the main protease of SARS-CoV-2: an in silico investigation

Rakib¹,

Nain

Sami

et al. 2021

Briefings in Bioinformatics

Self Cite

View full text Add to dashboard Cite

show abstract

“…In comparison to our study, only one of the previous studies used a pharmacophore modelling technique for finding potential LasR inhibitors [33]. In this study, the native ligand of LasR was used for searching the two most structurally similar compounds from the PubChem database.…”

Section: Discussionmentioning

confidence: 98%

“…Several studies have been conducted for finding potential inhibitors of LasR. They focused mostly on traditional remedies [31], 147 approved drugs and natural compounds from SuperNatural and SuperDrug databases [32], ZINC database [33,34], TimTec's Natural Derivatives Library [35], and traditional Chinese medicines [36]. In contrast, our research study focused on FDA-approved drugs from drugbank database [37].…”

Section: Discussionmentioning

confidence: 99%

Virtual Screening of FDA-Approved Drugs against LasR of Pseudomonas aeruginosa for Antibiofilm Potential

et al. 2020

View full text Add to dashboard Cite

Pseudomonas aeruginosa is a Gram-negative pathogenic bacterium that is present commonly in soil and water and is responsible for causing septic shock, pneumonia, urinary tract and gastrointestinal infections, etc. The multi-drug resistance (MDR) phenomenon has increased dramatically in past years and is now considered a major threat globally, so there is an urgent need to develop new strategies to overcome drug resistance by P. aeruginosa. In P. aeruginosa, a major factor of drug resistance is associated to the formation of biofilms by the LasR enzyme, which regulates quorum sensing and has been reported as a new therapeutic target for designing novel antibacterial molecules. In this study, virtual screening and molecular docking were performed against the ligand binding domain (LBD) of LasR by employing a pharmacophore hypothesis for the screening of 2373 FDA-approved compounds to filter top-scoring hit compounds. Six inhibitors out of 2373 compounds were found to have binding affinities close to that of known LasR inhibitors. The binding modes of these compounds to the binding site in LasR-LBD were analyzed to identify the key interactions that contribute to the inhibition of LasR activity. Then, 50 ns simulations of top hit compounds were performed to elucidate the stability of their binding conformations with the LasR-LBD. This study, thus concluded that sulfamerazine showed the highest binding affinity for the LasR-LBD binding pocket exhibiting strong inhibitory binding interactions during molecular dynamics (MD) simulation.

show abstract

“…Prime uses a surface generalized Born (SGB) model employing a Gaussian surface instead of van der Waals surface for better representation of a solvent accessible surface area. MM/ GBSA, provides better statistical correlations against experimental binding data than previous similar reported studies (Nain et al, 2019;Adasme-Carreño et al, 2014). The co-crystallized pose-viewer complexes were used as input files with implicit VSGB solvation model, OPLS3 force field and all other settings as default in Prime MM-GBSA (GlideScore/Docking Score doesn't correlate with my known activities.…”

Section: Mm-gbsa: Binding Free Energy Calculationmentioning

confidence: 99%

In-silico homology assisted identification of inhibitor of RNA binding against 2019-nCoV N-protein (N terminal domain)

Sarma

Shekhar

Prajapat

et al. 2020

Journal of Biomolecular Structure and Dynamics

184

187

View full text Add to dashboard Cite

The N terminal domain (NTD) of Nucleocapsid protein (N protein) of coronavirus (CoV) binds to the viral (þ) sense RNA and results in CoV ribonucleoprotien (CoV RNP) complex, essential for the virus replication. In this study, the RNA-binding N terminal domain (NTD) of the N protein was targeted for the identification of possible inhibitors of RNA binding. Two NTD structures of N proteins were selected (2OFZ and 1SSK, 92% homology) for virtual screening of 56,079 compounds from Asinex and Maybridge library to identify top 15 hits for each of the targets based on 'docking score'. These tophits were further screened for MM-GBSA binding free energy, pharmacokinetic properties (QikProp) and drug-likeness (SwissADME) and subjected to molecular dynamics (MD) studies. Two suitable binders (ZINC00003118440 and ZINC0000146942) against the target 2OFZ were identified. ZINC00003118440 is a theophylline derivative under the drug class 'bronchodilators' and further screening with approved bronchodilators was also studied to identify their ability to bind to the RNA binding region on the N protein. The other identified top hit is ZINC0000146942, which is a 3,4dihydropyrimidone class molecule. Hence this study suggests two important class of compounds, theophylline and pyrimidone derivaties as possible inhibitors of RNA binding to the N terminal domain of N protein of coronavirus, thus opening new avenues for in vitro validations.

show abstract

Energy-optimized pharmacophore coupled virtual screening in the discovery of quorum sensing inhibitors of LasR protein of Pseudomonas aeruginosa

Cited by 22 publications

References 83 publications

A molecular modelling approach for identifying antiviral selenium-containing heterocyclic compounds that inhibit the main protease of SARS-CoV-2: an in silico investigation

A molecular modelling approach for identifying antiviral selenium-containing heterocyclic compounds that inhibit the main protease of SARS-CoV-2: an in silico investigation

Virtual Screening of FDA-Approved Drugs against LasR of Pseudomonas aeruginosa for Antibiofilm Potential

In-silico homology assisted identification of inhibitor of RNA binding against 2019-nCoV N-protein (N terminal domain)

Contact Info

Product

Resources

About