Interactions between main protease of SARS-CoV-2 and testosterone or progesterone using computational approach

Vishvakarma, Vijay Kumar; Pal, Shweta; Singh, Prashant; Bahadur, Indra

doi:10.1016/j.molstruc.2021.131965

Cited by 22 publications

(9 citation statements)

References 43 publications

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“…To further analyze the dynamic atomic interactions of IPP/DMAPP within the active site, 100ns NudF and its complexes are simulated using WebGro, as shown recently(Vishvakarma et al 2021, Tumskiy and Tumskaia 2021). MD simulation is a robustly accurate strategy to analyze the configurational changes that occur when a ligand is induced to fit (Leach, 2007).…”

Section: Resultsmentioning

confidence: 99%

NudF-boosted strategy to improve the yield of DXS pathway

Prasanna

Runthala

Shantier

2022

Preprint

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Background: Terpenoids form a large pool of highly diverse organic compounds possessing several economically important properties, including nutritional, aromatic, and pharmacological properties. The DXP pathway's end enzyme, nuclear distribution protein (NudF), interacting with isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), is critical for the synthesis of isoprenol/prenol/downstream compounds. The enzyme is yet to be thoroughly investigated to increase the overall yield of terpenoids in the Bacillus subtilis, which is widely used in industry and is generally regarded as safe (GRAS) bacterium. The study aims to analyze the evolutionary conservation across the active site, and map the key residues for mutagenesis studies. The study would allow us customize the metabolic load towards the synthesis of prenol or isoprenol or any of the downstream molecules. Results: The 37-sequence dataset, extracted from 103 Bacillus subtilis entries, show a high phylogenetic divergence, and only six one-motif sequences ASB92783.1, ASB69297.1, ASB56714.1, AOR97677.1, AOL97023.1, and OAZ71765.1 show monophyly relationship, unlike a complete polyphyly relationship between the other 31 three-motif sequences. Further, only 47 of 179 residues of the representative sequence CUB50584.1 are observed to be significantly conserved. Docking analysis shows a preferential bias of ADP-ribose pyrophosphatase towards IPP, and a nearly 3-fold energetic difference is observed between IPP and DMAPP. Computational saturation mutagenesis of the seven hotspot residues identifies two key positions LYS78 and PHE116, encoded within loop1 and loop7, majorly interact with the ligands DMAPP and IPP, and their mutants K78I/K78L and PHE116D/PHE116E are found to stabilize the overall conformation. The loops are hereby shown to play a regulatory role in guiding the promiscuity of NudF towards a specific ligand. Conclusion: The study map the phylogenetic relationship between the 37 representative B.subtiis NudF sequences, and through sequence conservation, structural contact map, topological flexibility, and saturation mutagenesis of the active site residues, the essential residues regulating the interaction of NudF with IPP/DMAPP are deciphered. The study robustly screens its mutational landscape and localizes the two crucial residues LYS78 and PHE116 for directing the mutagenesis studies. The preliminary docking and simulation results also suggest a preferential bias of ADP-ribose pyrophosphatase towards IPP over DMAPP. The findings would pave the way for the development of novel enzyme variants with highly improved catalytic ability for the large-scale bioproduction of specific terpenoids with significant neutraceutical or commercial value.

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Section: Resultsmentioning

confidence: 99%

NudF-boosted strategy to improve the yield of DXS pathway

Prasanna

Runthala

Shantier

2022

Preprint

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“…To further analyze the dynamic atomic interactions of IPP/DMAPP within the active site, 100 ns NudF and its complexes are simulated using WebGro, as shown recently. , MD simulation is a robustly accurate strategy to analyze the conformational changes that occur when a ligand is induced to fit . Using the GROMACS-based Webgro server, the protein/complex system is computationally evolved using the classical mechanics algorithm for a short 100 ns timespan, and the conformational stability or binding affinity of a ligand is assessed across the simulation trajectory.…”

Section: Resultsmentioning

confidence: 99%

Computationally Decoding NudF Residues To Enhance the Yield of the DXP Pathway

Prasanna

Runthala

2022

ACS Omega

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Terpenoids form a large pool of highly diverse organic compounds possessing several economically important properties, including nutritional, aromatic, and pharmacological properties. The 1-deoxy- d -xylulose 5-phosphate (DXP) pathway’s end enzyme, nuclear distribution protein (NudF), interacting with isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), is critical for the synthesis of isoprenol/prenol/downstream compounds. The enzyme is yet to be thoroughly investigated to increase the overall yield of terpenoids in the Bacillus subtilis , which is widely used in industry and is generally regarded as a safe (GRAS) bacterium. The study aims to analyze the evolutionary conservation across the active site for mapping the key residues for mutagenesis studies. The 37-sequence data set, extracted from 103 Bacillus subtilis entries, shows a high phylogenetic divergence, and only six one-motif sequences ASB92783.1, ASB69297.1, ASB56714.1, AOR97677.1, AOL97023.1, and OAZ71765.1 show a monophyly relationship, unlike a complete polyphyly relationship between the other 31 three-motif sequences. Furthermore, only 47 of 179 residues of the representative sequence CUB50584.1 are observed to be significantly conserved. Docking analysis suggests a preferential bias of adenosine diphosphate (ADP)-ribose pyrophosphatase toward IPP, and a nearly threefold energetic difference is observed between IPP and DMAPP. The loops are hereby shown to play a regulatory role in guiding the promiscuity of NudF toward a specific ligand. Computational saturation mutagenesis of the seven hotspot residues identifies two key positions LYS78 and PHE116, orderly encoded within loop1 and loop7, majorly interacting with the ligands DMAPP and IPP, and their mutants K78I/K78L and PHE116D/PHE116E are found to stabilize the overall conformation. Molecular dynamics analysis shows that the IPP complex is significantly more stable than the DMAPP complex, and the NudF structure is very unstable. Besides showing a promiscuous binding of NudF with ligands, the analysis suggests its rate-limiting nature. The study would allow us to customize the metabolic load toward the synthesis of any of the downstream molecules. The findings would pave the way for the development of catalytically improved NudF mutants for the large-scale production of specific terpenoids with significant nutraceutical or commercial value.

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“…Molecular dynamics (MD) simulation study was performed using the GROMACS simulation program and the GROMOS96 43a1 force field was selected (Pol-Fachin et al 2009;Abraham et al 2015;Tumskiy and Tumskaia 2021;Kalimuthu et al 2021;Vishvakarma et al 2022).…”

Section: Molecular Dynamics Simulationsmentioning

confidence: 99%

Exploration of bioactive molecules from Tinospora cordifolia and Actinidia deliciosa as an immunity modulator via molecular docking and molecular dynamics simulation study

Bagal

Rathod

Mulla

et al. 2023

Natural Product Research

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Tinospora cordifolia and Actinidia deliciosa are the widely used plant in Ayurvedic systems of medicine. Both plants are well known for their immunomodulatory activity. In the current study, in silico exploration was performed using advanced computational techniques such as molecular docking and molecular dynamics simulation approach. Bioactive molecules from the Tinospora cordifolia and Actinidia deliciosa were docked against the Human IL-2. Out of all the docked bioactive molecules, Pygenic acid-B (PubChem CID:146157192) showed the highest negative binding affinity.

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Interactions between main protease of SARS-CoV-2 and testosterone or progesterone using computational approach

Cited by 22 publications

References 43 publications

NudF-boosted strategy to improve the yield of DXS pathway

NudF-boosted strategy to improve the yield of DXS pathway

Computationally Decoding NudF Residues To Enhance the Yield of the DXP Pathway

Exploration of bioactive molecules from Tinospora cordifolia and Actinidia deliciosa as an immunity modulator via molecular docking and molecular dynamics simulation study

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