<i>In silico</i> identification and screening of CYP24A1 inhibitors: 3D QSAR pharmacophore mapping and molecular dynamics analysis

Jayaraj, John Marshal; Gopinath, Krishnasamy; Lee, Jung-Kul; Muthusamy, Karthikeyan

doi:10.1080/07391102.2018.1464958

Cited by 29 publications

(14 citation statements)

References 30 publications

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“…The dynamic nature and protein–ligand stability of the three lead compounds were analyzed by a molecular dynamics study [ 70 ].…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, it was neutralized by adding Na + /Cl − ions. Energy minimization steps were carried out using a steepest descent method (50,000 steps), and NVT and NPT ensembles were also performed for 100 and 300 ps, respectively [ 70 ]. The long-range electrostatic interactions in the system were calculated by the Particle Mesh Ewald (PME) algorithm [ 78 ].…”

Section: Methodsmentioning

confidence: 99%

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In Silico Prediction, Molecular Docking and Dynamics Studies of Steroidal Alkaloids of Holarrhena pubescens Wall. ex G. Don to Guanylyl Cyclase C: Implications in Designing of Novel Antidiarrheal Therapeutic Strategies

et al. 2021

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The binding of heat stable enterotoxin (STa) secreted by enterotoxigenic Escherichia coli (ETEC) to the extracellular domain of guanylyl cyclase c (ECDGC-C) causes activation of a signaling cascade, which ultimately results in watery diarrhea. We carried out this study with the objective of finding ligands that would interfere with the binding of STa on ECDGC-C. With this view in mind, we tested the biological activity of a alkaloid rich fraction of Holarrhena pubescens against ETEC under in vitro conditions. Since this fraction showed significant antibacterial activity against ETEC, we decided to test the screen binding affinity of nine compounds of steroidal alkaloid type from Holarrhena pubescens against extracellular domain (ECD) by molecular docking and identified three compounds with significant binding energy. Molecular dynamics simulations were performed for all the three lead compounds to establish the stability of their interaction with the target protein. Pharmacokinetics and toxicity profiling of these leads demonstrated that they possessed good drug-like properties. Furthermore, the ability of these leads to inhibit the binding of STa to ECD was evaluated. This was first done by identifying amino acid residues of ECDGC-C binding to STa by protein–protein docking. The results were matched with our molecular docking results. We report here that holadysenterine, one of the lead compounds that showed a strong affinity for the amino acid residues on ECDGC-C, also binds to STa. This suggests that holadysenterine has the potential to inhibit binding of STa on ECD and can be considered for future study, involving its validation through in vitro assays and animal model studies.

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“…The dynamic nature and protein–ligand stability of the three lead compounds were analyzed by a molecular dynamics study [ 70 ].…”

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

In Silico Prediction, Molecular Docking and Dynamics Studies of Steroidal Alkaloids of Holarrhena pubescens Wall. ex G. Don to Guanylyl Cyclase C: Implications in Designing of Novel Antidiarrheal Therapeutic Strategies

et al. 2021

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“…The detailed information was reported on our previous work. 25 Three-dimensional structures of VDR and CYP24A1…”

Section: Computational Mutagenesis and Protein Preparationmentioning

confidence: 99%

“…Ketoconazole is the only drug approved by the FDA, and computational screened 3 hits of VDR and 3 hits of CYP24A1 were taken to ligand preparation. 25,26 All compounds were prepared and minimized using the OPLS3e force field in the Ligprep module of the maestro, Schrodinger 2018-4. 27…”

Section: Ligand Preparationmentioning

confidence: 99%

Structural and functional insights on vitamin D receptor and CYP24A1 deleterious single nucleotide polymorphisms: A computational and pharmacogenomics perpetual approach

Jayaraj

Kuriakose

Alhazmi

et al. 2021

Cell Biochemistry & Function

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The development of chronic kidney disease (CKD) drugs remains a challenge due to the variations in the genes. The vitamin D receptor (VDR) and Cytochrome 24A1 (CYP24A1) genetic variants might affect the drug potency, efficacy and pathway.Here we have to analyse and determine the deleterious single-nucleotide polymorphisms (nsSNPs) of VDR and CYP24A1 genes and their different population's drug responses in different populations to understand the key role in CKD. Among that the large scale of nsSNP, we used certain computational tools that predicted six missense variants are observed to be significantly damaging effect and SNP variability with large differences in various populations. Molecular docking studies were carried out by clinical and our screened compounds to VDR and CYP24A1. Docking results revealed all the compounds have a good binding affinity (Score). The screened compounds (TCM_2868 and UNPD_141613) show good binding affinity when compared to known compounds. The QM/MM study revealed that the compounds have electron transfer ability and act as a donor/acceptor to mutated proteins. The structural and conformational changes of protein complexes were analysed by molecular dynamics study. Hence, this study helps to identify suitable drugs through drug discovery in CKD treatment. The abovementioned compounds have more binding affinity, efficacy, and potency of both wild and mutant of VDR and CYP24A1.

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“…Finally, a 100 ns-long production MD simulation at a constant temperature of 300 K, maintained by the v-rescale thermostat, was performed. After MD simulations, the 100 ns dynamic structure was selected as a representative structure from each system to further analysis (Alaofi, 2020;Alaofi et al, 2017;Jayaraj et al, 2019).…”

Section: Simulationsmentioning

confidence: 99%

Exploring structural dynamics of the MERS-CoV receptor DPP4 and mutant DPP4 receptors

Alaofi

2020

Journal of Biomolecular Structure and Dynamics

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Mouse DPP4 (mDPP4) receptor is not a functional receptor for MERS-CoV while human DPP4 (hDPP4) is, despite the high similarities between hDPP4 and mDPP4 receptors. The variability of DPP4 receptors against MERS-CoV is not fully investigated, especially conformational and structural differences. Therefore, investigating the conformational differences of the DPP4 receptors can aid in developing new small animal models for MERS-CoV vaccines and antiviral agents evaluation. Here we used MD simulations and docking techniques to investigate these structural differences in DPP4 receptors. The results showed chimeric mouse mDPP4 (cmDPP4) has a similar compact conformation as wild-type hDPP4 based on the structural analysis. Interestingly, a single Thr288Ala mutation induced a relaxed conformation in chimeric 2 hDPP4 (c2hDPP4) and chimeric 2 mDPP4 (c2mDPP4); in addition to its significant effect on the DPP4 flexibility. The Thr288 residue is known for its critical function in MERS-CoV RBD interaction. Moreover, MERS-CoV RBD adopts a "standing" conformation when docked to hDPP4 and cmDPP4 in blade IV and V regions. In conclusion, the results could explain the functionality differences between mouse and human DPP4 receptors against MERS-CoV. However, further structural studies are needed to evaluate how DPP4 conformations affects MERS-CoV RBD binding and affinity.

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In silico identification and screening of CYP24A1 inhibitors: 3D QSAR pharmacophore mapping and molecular dynamics analysis

Cited by 29 publications

References 30 publications

In Silico Prediction, Molecular Docking and Dynamics Studies of Steroidal Alkaloids of Holarrhena pubescens Wall. ex G. Don to Guanylyl Cyclase C: Implications in Designing of Novel Antidiarrheal Therapeutic Strategies

In Silico Prediction, Molecular Docking and Dynamics Studies of Steroidal Alkaloids of Holarrhena pubescens Wall. ex G. Don to Guanylyl Cyclase C: Implications in Designing of Novel Antidiarrheal Therapeutic Strategies

Structural and functional insights on vitamin D receptor and CYP24A1 deleterious single nucleotide polymorphisms: A computational and pharmacogenomics perpetual approach

Exploring structural dynamics of the MERS-CoV receptor DPP4 and mutant DPP4 receptors

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