Investigating potency of TMC-126 against wild-type and mutant variants of HIV-1 protease: a molecular dynamics and free energy study

Sk, Md Fulbabu; Haridev, S; Roy, Rajarshi; Kar, Parimal

doi:10.1080/1062936x.2021.1999318

Cited by 6 publications

(2 citation statements)

References 73 publications

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“…The molecular mechanics Poisson–Boltzmann (generalized Born) surface area (MM-PB(GB)SA) scheme [ 38 – 42 ] is widely used to determine the binding free energy between protein-inhibitor [ 14 , 43 ], protein-nucleic acid [ 44 – 46 ] as well as protein-carbohydrate [ 47 , 48 ] complexes. The total binding free energy comprises internal energy desolvation free energy , and configurational entropy which are related by the following equation [ 16 , 49 – 53 ], …”

Section: Methodsmentioning

confidence: 99%

Computational studies indicated the effectiveness of human metabolites against SARS-Cov-2 main protease

Roy

Tanwar³

et al. 2022

Mol Divers

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To fight against the devastating coronavirus disease 2019 (COVID-19), identifying robust anti-SARS-CoV-2 therapeutics from all possible directions is necessary. To contribute to this effort, we selected a human metabolites database containing waters and lipid-soluble metabolites to screen against the 3-chymotrypsin-like proteases (3CL pro ) protein of SARS-CoV-2. The top 8 hits from virtual screening displayed a docking score varying between ~ − 11 and ~ − 14 kcal/mol. Molecular dynamics simulations complement the virtual screening study in conjunction with the molecular mechanics generalized Born surface area (MM/GBSA) scheme. Our analyses revealed that (HMDB0132640) has the best glide docking score, − 14.06 kcal/mol, and MM-GBSA binding free energy, − 18.08 kcal/mol. The other three lead molecules are also selected along with the top molecule through a critical inspection of their pharmacokinetic properties. HMDB0132640 displayed a better binding affinity than the other three compounds (HMDB0127868, HMDB0134119, and HMDB0125821) due to increased favorable contributions from the intermolecular electrostatic and van der Waals interactions. Further, we have investigated the ligand-induced structural dynamics of the main protease. Overall, we have identified new compounds that can serve as potential leads for developing novel antiviral drugs against SARS-CoV-2 and elucidated molecular mechanisms of their binding to the main protease. Graphical abstract Identification of probable hits from human metabolites against SARS-CoV-2 using integrated computational approaches-Missed against MS Supplementary Information The online version contains supplementary material available at 10.1007/s11030-022-10513-6.

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Section: Methodsmentioning

confidence: 99%

Computational studies indicated the effectiveness of human metabolites against SARS-Cov-2 main protease

Roy

Tanwar³

et al. 2022

Mol Divers

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“…We considered dielectric constants of 1.0 and 80.0 for the solute and solvent, respectively. A detailed protocol of the MM/PBSA scheme was discussed in our previous works. ,, We have used 3000 frames extracted from the last 300 ns trajectory for MM/PBSA calculation. We have neglected the configurational entropy ( T Δ S ) due to high computational cost.…”

Section: Methodsmentioning

confidence: 99%

Phosphorylation-Induced Conformational Dynamics and Inhibition of Janus Kinase 1 by Suppressors of Cytokine Signaling 1

Jonniya

Roy

et al. 2022

J. Phys. Chem. B

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The dysfunction of the JAK/STAT (Janus kinase/ signal transducers and activators of transcription) pathway results in several pathophysiological conditions, including autoimmune disorders. The negative feedback regulators of the JAK/STAT signaling pathway, suppressors of cytokine signaling (SOCS), act as a natural inhibitor of JAK and inhibit aberrant activity. SOCS1 is the most potent member of the SOCS family, whose kinase inhibitory region targets the substrate-binding groove of JAK with high affinity and blocks the phosphorylation of JAK kinases. Overall, we performed an aggregate of 13 μs molecular dynamics simulations on the activation loop's three different phosphorylation (double and single) states. Results from our simulations show that the single Tyr 1034 phosphorylation could stabilize the JAK1/ SOCS1 complex as well as the flexible activation segment. The phosphate-binding loop (P-loop) shows conformational variability at dual and single phosphorylated states. Principal component analysis and protein structure network (PSN) analysis reveal that the different phosphorylation states and SOCS1 binding induce intermediate inactive conformations of JAK1, which could be a better target for future JAK1 selective drug design. PSN analysis suggests that the com-pY1034 system is stabilized due to higher values of network hubs than the other two complex systems. Moreover, the binding free energy calculations suggest that pTyr 1034 states show a higher affinity toward SOCS1 than the dual and pTyr 1035 states. We believe that the mechanistic understanding of JAK1/SOCS1 complexation will aid future studies related to peptide inhibitors based on SOCS1.

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Plant-derived active compounds as a potential nucleocapsid protein inhibitor of SARS-CoV-2: anin-silicostudy

Kashyap

Roy

Kar

et al. 2022

Journal of Biomolecular Structure and Dynamics

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Investigating potency of TMC-126 against wild-type and mutant variants of HIV-1 protease: a molecular dynamics and free energy study

Cited by 6 publications

References 73 publications

Computational studies indicated the effectiveness of human metabolites against SARS-Cov-2 main protease

Computational studies indicated the effectiveness of human metabolites against SARS-Cov-2 main protease

Phosphorylation-Induced Conformational Dynamics and Inhibition of Janus Kinase 1 by Suppressors of Cytokine Signaling 1

Plant-derived active compounds as a potential nucleocapsid protein inhibitor of SARS-CoV-2: anin-silicostudy

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