Molecular Dynamic Simulation and Docking of Cyclophilin A Mutants with its Potential Inhibitors

Mohebbi, Alireza; Mirarab, Azam; Shaddel, Reyhane; Fallah, Mahnaz Shafaei; Memarian, Ali

doi:10.52547/jcbr.5.2.26

Cited by 5 publications

(7 citation statements)

References 34 publications

(30 reference statements)

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“…Moreover, the protocol of this work can be employed for further drug discovery on either HBV or other clinically important viral diseases. Additionally, the molecular dynamic simulation (MDS) [ 33 , 43 ] study can uncover the stability of highlighted compounds on induction of structural instability of HBV core and to further decipher the mechanism(s) of CAMs on malformed HBV capsid formation.…”

Section: Discussionmentioning

confidence: 99%

“…The toxicity of the chemicals was also assessed by the toxicity estimation software tool (T.E.S.T) [ 32 ]. In this regard, the nearest neighbor method was used to predict Fathead minnow LC 50 (96 hr), Daphnia magna LC 50 (48 hr), Tetrahymena pyriformis IGC 50 (48 hr), Oral rat LC 50 , Bioaccumulation factor, and Ames mutagenicity as previously shown [ 33 ].…”

Section: Methodsmentioning

confidence: 99%

“…The decoys were generated by the Directory of Useful Decoys- Enhanced (DUD-E) server [ 36 , 37 ]. The affinity of the training and test sets of small molecules were predicted by Autodock Vina [ 38 ] as described before [ 27 , 33 ] and used as the dependent variable. Descriptors with a probability of entry of ≤ 0.01 were selected as independent variables, and the model was developed with a confidence interval (CI) of 95%.…”

Section: Methodsmentioning

confidence: 99%

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A fragment-based drug discovery developed on ciclopirox for inhibition of Hepatitis B virus core protein: An in silico study

Mohebbi,

Ghorbanzadeh,

Naderifar

et al. 2023

PLoS ONE

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The Hepatitis B virus (HBV) core protein is an attractive target for preventing capsid assembly and viral replication. Drug repurposing strategies have introduced several drugs targeting HBV core protein. This study used a fragment-based drug discovery (FBDD) approach to reconstruct a repurposed core protein inhibitor to some novel antiviral derivatives. Auto Core Fragment in silico Screening (ACFIS) server was used for deconstruction-reconstruction of Ciclopirox in complex with HBV core protein. The Ciclopirox derivatives were ranked based on their free energy of binding (ΔGB). A quantitative structure affinity relationship (QSAR) was established on the Ciclopirox derivatives. The model was validated by a Ciclopirox-property-matched decoy set. A principal component analysis (PCA) was also assessed to define the relationship of the predictive variable of the QSAR model. 24-derivatives with a ΔGB (-16.56±1.46 Kcal.mol-1) more than Ciclopirox was highlighted. A QSAR model with a predictive power of 88.99% (F-statistics = 9025.78, corrected df(25), Pr > F = 0.0001) was developed by four predictive descriptors (ATS1p, nCs, Hy, F08[C-C]). The model validation showed no predictive power for the decoy set (Q2 = 0). No significant correlation was observed between predictors. By directly attaching to the core protein carboxyl-terminal domain, Ciclopirox derivatives may be able to suppress HBV virus assembly and subsequent viral replication inhibition. Hydrophobic residue Phe23 is a critical amino acid in the ligand binding domain. These ligands share the same physicochemical properties that lead to the development of a robust QSAR mode. The same strategy may also be used for future drug discovery of viral inhibitors.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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A fragment-based drug discovery developed on ciclopirox for inhibition of Hepatitis B virus core protein: An in silico study

Mohebbi,

Ghorbanzadeh,

Naderifar

et al. 2023

PLoS ONE

Self Cite

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“…The following commands are implemented to determine the global solution of the Schrödinger equation for the determination of deposition and electrodeposition [ [7] , [8] ].…”

Section: Experimental Design Materials and Methodsmentioning

confidence: 99%

Source code and simulation data for the prediction of the electrodeposition mechanism of nanostructured metallic coatings

Rosano-Ortega

Bedolla-Hernández

et al. 2023

Data in Brief

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“…To encompass the druggable cavity, a grid box parameter was determined using MGLTools v1.5.7 [54,55]. A cut-off was measured by a same process of docking, determining the affinity of the ligands within the crystallographic structures to HBc monomer.…”

Section: Molecular Dockingmentioning

confidence: 99%

Computational-Aided Reproposing Drug(s) and Discovery for Potential Antivirals Targeting Hepatitis B Virus Capsid Protein

Mohebbi,

Naderi,

Sharifian

et al. 2023

Preprint

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Background: Chronic Hepatitis B Virus (HBV) infection is a global health concern, associated with severe liver diseases, necessitating ongoing research on novel drug candidates. This study aims to identify potential drug candidates targeting HBV core protein (HBcAg) and disrupting capsid assembly, a critical step in the virus's life cycle. Methods: HBcAg in complex with HBV inhibitors were obtained from the Protein Data Bank (PDB). CavityPlus server was used for analysis of druggable cavity. Structure-based pharmacophores were extracted from identified cavities, and potential allosteric ligand binding sites were assessed using CavPharmer, CorrSite, and CovCys. LigandScout was employed for ligand-based pharmacophore screening against an FDA-approved library. The ZINC database was screened with features extracted from CavPharmer. Molecular docking studies were conducted using Autodock Vina. Lead compounds were selected based on docking scores, binding modes, and interactions within the druggable cavity. Results: Strong druggable pockets were found for Ciclopirox, while Compound 24, NVR10-001E2, and others showed medium to weak pockets. Ligand-based pharmacophores varied in size and complexity. Screening revealed potential hits matching these pharmacophores, including Ciclopirox olamine, Voriconazole, Enasidenib, and Statins. A large compound database search yielded additional hits like ZINC86859997 and ZINC63280172. Docking analyses confirmed these hits' potential, highlighting their interactions with critical HBc protein residues, offering promising leads for hepatitis B drug development. Conclusions: Voriconazole, Enasidenib, and Lovastatin have shown promises. These hits displayed favorable interactions with crucial HBc protein residues, indicating their potential as lead compounds The mechanism of action of statins with anti-HBV activities also highlighted. This comprehensive approach offers valuable insights into targeting HBc protein for antiviral drug discovery.

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Molecular Dynamic Simulation and Docking of Cyclophilin A Mutants with its Potential Inhibitors

Cited by 5 publications

References 34 publications

A fragment-based drug discovery developed on ciclopirox for inhibition of Hepatitis B virus core protein: An in silico study

A fragment-based drug discovery developed on ciclopirox for inhibition of Hepatitis B virus core protein: An in silico study

Source code and simulation data for the prediction of the electrodeposition mechanism of nanostructured metallic coatings

Computational-Aided Reproposing Drug(s) and Discovery for Potential Antivirals Targeting Hepatitis B Virus Capsid Protein

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