Combined 3D-QSAR, molecular docking and molecular dynamics study on the benzimidazole inhibitors targeting HCV NS5B polymerase

Wang, Zhiguo; Chen, Zhenming; Li, Jianfeng; Huang, Jing; Zheng, Chenni; Liu, Junping

doi:10.1080/07391102.2019.1593244

Cited by 14 publications

(5 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The other force field parameters of CoA analogs were generated from the Generalized Amber Force field (GAFF) with the Antechamber module of Amber Tools ( Wang et al, 2004 ). Finally, by following the same procedure in our previous report ( Wang et al, 2019 ), MD simulations were conducted with varied time scales, i.e., 200 ns for MCT-CoA and 300 ns for MCT-mesaconyl-C1-CoA/mesaconyl-C4-CoA binding structures.…”

Section: Methodsmentioning

confidence: 99%

Crystal Structure of an Intramolecular Mesaconyl-Coenzyme A Transferase From the 3-Hydroxypropionic Acid Cycle of Roseiflexus castenholzii

Min

Zhang

et al. 2022

Front. Microbiol.

Self Cite

View full text Add to dashboard Cite

Coenzyme A (CoA) transferases catalyze reversible transfer of CoA groups from CoA-thioesters to free acids, playing important roles in the metabolism of carboxylic acids in all organisms. An intramolecular CoA transferase, Mesaconyl-CoA C1-C4 CoA transferase (MCT) was identified in the autotrophic CO2 fixation pathway, 3-hydroxypropionic acid cycle of filamentous anoxygenic phototrophs (FAPs). Different from the well-known CoA transferases that catalyze CoA transfer between two distinct substrates, MCT specifically catalyzes the reversible transformation of mesaconyl-C1-CoA to mesaconyl-C4-CoA, a key reaction intermediate for carbon fixation. However, the molecular mechanism of MCT in employing one substrate is enigmatic. Here we determined the crystal structure of MCT from a chlorosome-less FAP Roseiflexus castenholzii at 2.5 Å resolution, and characterized the catalytic mechanisms through structural analyses and molecular dynamic simulations. The structure of R. castenholzii MCT consists of a Rossmann fold larger domain and a small domain that are connected by two linkers. Two MCT subunits are cross interlocked at the linker regions to form a functional dimer in solution, in which the substrate binding pockets are located at the interface of the Rossmann fold larger domain from one subunit and the small domain from the other subunit. In the simulated binding structures, both the substrate mesaconyl-C1-CoA and product mesaconyl-C4-CoA form extensive electrostatic and hydrogen bonding interactions with MCT. But some differences exist in the binding mode of these two CoA analogs, Arg314’ from the second subunit of the dimer presenting dramatic conformational changes in binding with mesaconyl-C4-CoA. Together with Arg47 and one water molecule, a strictly conserved residue Asp165 are essential for catalyzing the reversible intramolecular CoA transfer reaction, through the electrostatic and hydrogen bonding interactions with the mesaconic tail of both the substrate and product. This study revealed a previously unrecognized mechanism for the uncommon intramolecular CoA transfer reaction, which will not only broaden the knowledge on the catalytic mechanisms of CoA transferases, but also contribute to enzyme engineering or biosynthetic applications of the 3-HP cycle for synthesis of fine chemicals and important metabolites.

show abstract

Section: Methodsmentioning

confidence: 99%

Crystal Structure of an Intramolecular Mesaconyl-Coenzyme A Transferase From the 3-Hydroxypropionic Acid Cycle of Roseiflexus castenholzii

Min

Zhang

et al. 2022

Front. Microbiol.

Self Cite

View full text Add to dashboard Cite

show abstract

“…For instance, Wang et al, 2014 developed QSAR based predictive models using SVM and MLR approaches using 333 NS5B inhibitors, obtaining correlation coefficient of 0.91 [50] . Similarly, Z. Wang et al, 2020 used comparative molecular field and similarity indices analysis for NS5B inhibitors identification and achieved 0.74 to 0.91 correlation coefficient [51] . In addition, a few classification based methods are also available.…”

Section: Discussionmentioning

confidence: 99%

Targeting non-structural proteins of Hepatitis C virus for predicting repurposed drugs using QSAR and machine learning approaches

Kamboj

Rajput

Rastogi

et al. 2022

Computational and Structural Biotechnology Journal

View full text Add to dashboard Cite

“…MD simulations were performed using the AMBER 12 software 64 . The FF14SB force field was applied for the CvFAP protein 65 , the reported parameter for the FAD was used 66 , and the restricted electrostatic potential (RESP) atomic charges and the force field parameters generated using the Antechamber module of AmberTools were applied for different target compounds 67 . The CvFAP proteins and the binding complexes were individually immersed into the center of a truncated octahedron box of TIP3P water molecules with a margin distance of 12.0 Å, Na + counterions were added by using the AMBER TLEAP module to keep system in electric neutrality 64 .…”

Section: Methodsmentioning

confidence: 99%

Light-driven decarboxylative deuteration enabled by a divergently engineered photodecarboxylase

Fan

Lou

et al. 2021

Nat Commun

Self Cite

View full text Add to dashboard Cite

Despite the well-established chemical processes for C-D bond formation, the toolbox of enzymatic methodologies for deuterium incorporation has remained underdeveloped. Here we describe a photodecarboxylase from Chlorella variabilis NC64A (CvFAP)-catalyzed approach for the decarboxylative deuteration of various carboxylic acids by employing D2O as a cheap and readily available deuterium source. Divergent protein engineering of WT-CvFAP is implemented using Focused Rational Iterative Site-specific Mutagenesis (FRISM) as a strategy for expanding the substrate scope. Using specific mutants, several series of substrates including different chain length acids, racemic substrates as well as bulky cyclic acids are successfully converted into the deuterated products (>40 examples). In many cases WT-CvFAP fails completely. This approach also enables the enantiocomplementary kinetic resolution of racemic acids to afford chiral deuterated products, which can hardly be accomplished by existing methods. MD simulations explain the results of improved catalytic activity and stereoselectivity of WT CvFAP and mutants.

show abstract

Combined 3D-QSAR, molecular docking and molecular dynamics study on the benzimidazole inhibitors targeting HCV NS5B polymerase

Cited by 14 publications

References 57 publications

Crystal Structure of an Intramolecular Mesaconyl-Coenzyme A Transferase From the 3-Hydroxypropionic Acid Cycle of Roseiflexus castenholzii

Crystal Structure of an Intramolecular Mesaconyl-Coenzyme A Transferase From the 3-Hydroxypropionic Acid Cycle of Roseiflexus castenholzii

Targeting non-structural proteins of Hepatitis C virus for predicting repurposed drugs using QSAR and machine learning approaches

Light-driven decarboxylative deuteration enabled by a divergently engineered photodecarboxylase

Contact Info

Product

Resources

About