Discovery Of Novel Casein Kinase-1Delta Inhibitors By ... ... Discovery of Novel Casein...

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  • Discovery of Novel Casein Kinase-1δ Inhibitors by

    Structure Based Virtual Screening, ADMET Analysis and

    Molecular Dynamics Simulation to Target Alzheimer's

    Disease

    Bhanwar Singh Choudhary* 1, Ruchi Malik1, Shubham Srivastava1

    1Department of Pharmacy, Central University of Rajasthan, Ajmer, India

    Bhanwar Singh Choudhary (CSIR-SRF),

    Dr Ruchi Malik’s Research Group

    Department of Pharmacy,

    Central University of Rajasthan, Ajmer,

    Rajasthan, India - 305817

  • Introduction

    • Alzheimer’s disease (AD) is a growing public health problem among the elderly.

    According to WHO, the number of affected people aged 65 or older were projected

    to grow from an estimated 524 million in 2010 to nearly 1.5 billion by 2050, with

    developing countries affected the most.

    • CK1δ is a potential target for AD, over activity of CK1δ may be regulated by an

    inhibitor without affecting its basic activity in cells.

    • CK1δ directly phosphorylated tubulin binding site of tau protein, which indicate its

    importance in tau aggregation. CK1δ and GSK-3 phosphorylate at least 15 sites in

    the paired helicoidal filaments (PHF) of tau in Alzheimer brain.

    2

  • 3

    Figure 1: Mechanism of neurofibrillary tangles formation in Alzheimer’s disease and

    promising drug target site

  • 4

    CK-1 δ Inhibitors

  • Methodology

    • Virtual screening: The protocol encompasses standard protocols provided by

    Schrodinger for virtual screening of large databases using HTVS, SP, XP and MM-

    GBSA.

    • ADMET: QikProp was used for ADME prediction was performed and reported for

    screened compounds. ADMET predictor version 7.1 was used to calculate toxicity

    for best scoring inhibitors obtained from MM-GBSA study and PF-4800567.

    • Molecular Dynamics: Full-atom MD simulations were performed for each system

    by using Desmond version 2014.2 (Maestro, version 10.4).

    5

  • 6 Figure 2: Graphical representation of methodology

  • Validation of Protein

    Enrichment calculation: Enrichment based ROC graph of the docking results was

    plotted between true positive rate (sensitivity) and false positive rate (1-specificity).

    ROC graph reflects the probability of a higher rank of randomly selected active

    compound.

    Table 1: Values of ROC and BEDROC calculated for SP docking results

    7

    S No. PDB ID ROC BEDROC (α 160.9)

    1 4HNF 0.74 0.201

    2 3UYT 0.65 0.205

    Result and Discussion

  • Validation of docking protocol

    Docking protocol was validated by structure guided binding pattern overlap of the

    co-crystallized and docked molecule i.e. PF4800567. The RMSD was found to be

    1.7358 Å (figure 3).

    8

    Figure 3: Superimposed co-crystallized (green) and docked (grey) PF4800567.

  • 9

    Table 1: MM-GBSA dG score, dock score and interacting residues of best hits.

    S. No. Zinc ID MM-GBSA Score Dock Score Interacting Residues

    1 PF4800567 -95.639 -10.444 Glu83, Leu85

    2 ZINC09036109 -115.578 -11.954 Leu85, Asp149

    3 ZINC72371723 -109.652 -12.415 Lys38, Tyr56, Leu85

    4 ZINC72371725 -109.16 -12.321 Lys38, Tyr56, Leu85

    5 ZINC19698731 -108.93 -11.611 Glu83, Leu85

    6 ZINC01373165 -107.224 -12.258 Leu85

    Virtual Screening

  • 10

    S.

    No.

    Molecule

    Name PolrZ

    Log

    Po/w logS Pcaco

    Log

    BB

    Log

    Kp Metab HOA

    Rule

    of 5 MDCK

    Range 13/70 -2.5

    /6.5

    -6.5

    /0.5

    25

    />500

    -3

    /1.2 -8/-1 1/8

    1L,

    2M,

    3H

    Max

    4 25 />500

    1 PF4800567 36.14 3.3 -4.8 1351.8 -0.4 -2.0 4 3 0 1689.7

    2 ZINC09036109 52.9 6.7 -8.1 1693.5 -0.7 -0.9 6 1 1 1244.8

    3 ZINC72371723 48.4 5.6 -6.5 583.9 0.1 -2.8 6 1 1 746.4

    4 ZINC72371725 48.3 5.6 -6.5 581.7 0.1 -2.8 6 1 1 751.8

    5 ZINC19698731 44.4 1.3 -2.6 40.3 -1.4 -3.4 6 2 0 223.2

    6 ZINC01373165 48.0 3.7 -4.0 110.7 -0.9 -4.1 8 3 0 50.7

    Table 2: ADME properties prediction of CK1δ inhibitors using QikProp

    In-silico ADMET Studies

  • 11

    S. No Molecule Name hERG PHOS AlkPos GGT LDH SGOT SGPT

    1 PF4800567 T NT T NT NT T NT

    2 ZINC09036109 NT NT NT NT T T T

    3 ZINC72371723 T NT T NT NT NT NT

    4 ZINC72371725 T NT T NT NT NT NT

    5 ZINC19698731 NT NT T NT T T NT

    6 ZINC01373165 NT NT NT T NT T T

    Table 3: Toxicity prediction of CK1δ inhibitors using ADMET predictor

  • 12

    Molecular Dynamics Studies

    Figure 4a: RMSD and RMSF of protein ligand complex CK1δ-ZINC09036109

  • 13 Figure 4b: RMSD and RMSF of protein ligand complex CK1δ-ZINC01373165

  • 14 Figure 4c: RMSD and RMSF of protein ligand complex CK1δ-PF4800567

  • 15

    Figure 5a: 2D Molecular interaction diagram and Protein-Ligand contacts of

    ZINC09036109 with amino acid residues of CK1δ

  • 16 Figure 5b: 2D Molecular interaction diagram and Protein-Ligand contacts of

    ZINC01373165 with amino acid residues of CK1δ

  • 17

    Figure 5c: 2D Molecular interaction diagram and Protein-Ligand contacts of PF4800567

    with amino acid residues of CK1δ

  • Conclusion

    • These studies reveal that ZINC09036109, ZINC19698731 and ZINC01373165 will

    be approaching optimal ADMET properties along with good dG bind score. Co-

    crystallized PF4800567 was toxic to hERG whereas, three screened hits are

    expected to show less toxicity potential.

    • Molecular dynamics simulation explains that ZINC09036109 and ZINC01373165

    have good selectivity for CK1δ on the basis of key residues interactions.

    18

  • • Department of Science & Technology (DST) -Rajasthan for Research

    Support.

    • DST-Rajasthan and Council of Scientific & Industrial Research (CSIR) –

    India for fellowship.

    • Indian Council for Medical Research (ICMR) for Travel Support.

    • Central University of Rajasthan for Infrastructural facilities.

    19

    Acknowledgment

  • THANK YOU

    20

    Dr. Ruchi Malik: [email protected] Mr. Bhanwar Singh: [email protected] [email protected]

    mailto:[email protected] mailto:[email protected] mailto:[email protected]