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. 2023 Mar 2:17:11779322231158254.
doi: 10.1177/11779322231158254. eCollection 2023.

Pharmacophore-Aided Virtual Screening and Molecular Dynamics Simulation Identifies TrkB Agonists for Treatment of CDKL5-Deficiency Disorders

Ibitayo Abigail Ademuwagun  1   2 , Gbolahan Oladipupo Oduselu  1   3 , Solomon Oladapo Rotimi  1   2 , Ezekiel Adebiyi  1   4   5
Affiliations

Pharmacophore-Aided Virtual Screening and Molecular Dynamics Simulation Identifies TrkB Agonists for Treatment of CDKL5-Deficiency Disorders

Ibitayo Abigail Ademuwagun et al. Bioinform Biol Insights. .

Abstract

Therapeutic intervention in cyclin-dependent kinase-like 5 (CDKL5) deficiency disorders (CDDs) has remained a concern over the years. Recent advances into the mechanistic interplay of signalling pathways has revealed the role of deficient tropomyosin receptor kinase B (TrkB)/phospholipase C γ1 signalling cascade in CDD. Novel findings showed that in vivo administration of a TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF), resulted in a remarkable reversal in the molecular pathologic mechanisms underlying CDD. Owing to this discovery, this study aimed to identify more potent TrkB agonists than 7,8-DHF that could serve as alternatives or combinatorial drugs towards effective management of CDD. Using pharmacophore modelling and multiple database screening, we identified 691 compounds with identical pharmacophore features with 7,8-DHF. Virtual screening of these ligands resulted in identification of at least 6 compounds with better binding affinities than 7,8-DHF. The in silico pharmacokinetic and ADMET studies of the compounds also indicated better drug-like qualities than those of 7,8-DHF. Postdocking analyses and molecular dynamics simulations of the best hits, 6-hydroxy-10-(2-oxo-1-azatricyclo[7.3.1.05,13]trideca-3,5(13),6,8-tetraen-3-yl)-8-oxa-13,14,16-triazatetracyclo[7.7.0.02,7.011,15]hexadeca-1,3,6,9,11,15-hexaen-5-one (PubChem: 91637738) and 6-hydroxy-10-(8-methyl-2-oxo-1H-quinolin-3-yl)-8-oxa-13,14,16-triazatetracyclo[7.7.0.02,7.011,15]hexadeca-1,3,6,9,11,15-hexaen-5-one (PubChem ID: 91641310), revealed unique ligand interactions, validating the docking findings. We hereby recommend experimental validation of the best hits in CDKL5 knock out models before consideration as drugs in CDD management.

Keywords: CDKL5 deficiency disorders; molecular dynamics simulation; pharmacophore; seizure; virtual screening.

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Conflict of interest statement

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
X-ray crystallographic structure of the ligand binding domain of TrkB receptor., TrkB indicates tropomyosin receptor kinase B.
Figure 2.
Figure 2.
Structure of 7,8-DHF. 7,8-DHF indicates 7,8-dihydroxyflavone.
Figure 3.
Figure 3.
Interactions of 7,8-DHF with 5 specific residues on TrkB ligand binding domain: (A) 2D interactions and (B) 3D interactions. 2D indicates two dimension; 7,8-DHF 7,8-dihydroxyflavone; 3D, three dimension; TrkB, tropomyosin receptor kinase B.
Figure 4.
Figure 4.
RMSD time series: (A) 1wwb protein and (B) compound 1. RMSD histogram: (C) 1wwb protein and (D) compound 1. RMSD indicates root mean square deviation.
Figure 5.
Figure 5.
RMSD time series: (A) 1wwb protein and (B) compound 2. RMSD histogram: (C) 1wwb protein and (D) compound 2. RMSD indicates root mean square deviation.
Figure 6.
Figure 6.
RMSF versus residue position: (A) compound 1 and (B) compound 2. RMSF indicates root mean square fluctuation.
Figure 7.
Figure 7.
PCA results for the protein backbone in the 1wwb complex, comprising graphs of PC2 versus PC1, PC2 versus PC3, and PC3 versus PC1, and an eigenvalue rank plot with the cumulative variance annotated for each data point: (A) compound 1 and (B) compound 2. PCA indicates principal components analysis.
Figure 8.
Figure 8.
Hydrogen bond graph of compound 1 in the active site of 1wwb during simulation.
Figure 9.
Figure 9.
Hydrogen bond graph of compound 2 in the active site of 1wwb during simulation.
See this image and copyright information in PMC

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