Embed Size (px)
Citation preview
Chemotype-based Designing of Mycobacterium tuberculosis
BioA inhibitors: Docking studies and ADME analysis Aparna Bahuguna, Shiv Shyam Maurya, Deepak Kumar, Prija Ponnan, Diwan S. Rawat*
Department of Chemistry, University of Delhi, Delhi-110007, India
E-mail: [email protected]
Adenosylmethionine-8-amino-7-oxononanoate aminotransferase (BioA),a PLP-dependent transaminase of M. tuberculosis (Mtb),
catalyzes the reversible transfer of the α-amino group from SAM to KAPA to form DAPA.
7-Keto-8-aminopelargonic acid
(KAPA)
7,8-Diaminopelargonic acid
(DAPA)
S-Adenosyl-(2-oxo-4-thiobutyrate) S-Adenosylmethionine (SAM)
BioA
Crystal structure bound to
KAPA (PDB ID: 4CXQ) showing
H-bond interactions residues
Tyr25, Trp64, Arg400, Tyr157,
Gly316 and covalent interaction
With co-factor PLP.
BioA has recently gained much importance as anti-TB drug target for its
specificity in Mtb and absence of the enzyme in higher eukaryotic organisms
such as plants and mammals. Hence,t here has been considerable effort in
identifying novel lead molecule as BioA inhibitors.
Active Site of Mtb BioA
Bioactive conformation of KAPA ABA-604
ABA-601
ABA-603
ABA-600 SSM-7
ABA-3
ABA-30
ABA-100
ABA-101
ABA-602
mol_MW :334.43,QPlogPo/w: 1.13, DonorHB:3,
AccptHB:9
PSA: 92.41
#rotor:7
QPlogHERG: -6.382
QPlogKhsa: -0.366
PercentHumanOralAbsorption:68.708
QPPCaco: 91.842
mol_MW: 441.435,QlogPo/w: 2.775,DonorHB: 1
AccptHB: 6
#Rotor: 6
QPlogHERG: -6.71
QPPCaco: 17.56
QPlogKhsa: 0.42
HumanOralAbsorption: 3
mol_MW : 290.318,QPlogPo/w:5, DonorHB:0,
AccptHB:4.75
PSA: 76.445
#rotor:5
QPlogHERG: 76.445
QPlogKhsa: -0.13
PercentHumanOralAbsorption: 91.974
QPPCaco: 656.433
mol_MW :311.383,QPlogPo/w:1.009 DonorHB:1,
AccptHB:1.75
PSA:76.464
#rotor:2
QPlogHERG:-4.551
QPlogKhsa:-0.398
PercentHumanOralAbsorption:
QPPCaco:131.385
Mol_MW: 360.52, QlogPo/w: 2.58, DonorHB: 1
AccptHB: 8
#rotor: 7
QPlogHERG: -7.27
QPPCaco: 164.29
QPlogKhsa: 0.09
HumanOralAbsorption: 3.00
mol_MW: 304.39, QlogPo/w: 3.42,DonorHB: 1
AccptHB: 5
#rotor: 3
QPlogHERG: -5.22
QPPCaco: 779.82
QPlogKhsa: 0.49
HumanOralAbsorption: 1.00
mol_MW 347.30, QlogPo/w: 2.93,DonorHB: 2
AccptHB: 6
# rotor: 3
QPlogHERG: -5.96
QPPCaco: 530.44
QPlogKhsa: 0.08
HumanOralAbsorption: 3.00
mol_MW: 270.33, QlogPo/w: 0.23,DonorHB: 2
AccptHB:7
# Rotor: 3
QPlogHERG: -4.22
QPPCaco: 35.18
QPlogKhsa: -0.53
HumanOralAbsorption: 2.00
mol_MW: 341.46, QlogPo/w: 2.58,DonorHB: 1
AccptHB: 7
#rotor: 5
QPlogHERG: -7.85
QPPCaco: 85.63
QPlogKhsa: 0.33
HumanOralAbsorption: 3.00
Mol_MW: 355.48, QlogPo/w: 2.64,DonorHB: 1
AccptHB: 7
# rotor: 5
QPlogHERG: -7.42
QPPCaco: 89.29
QPlogKhsa: 0.36
HumanOralAbsorption: 3.00
KAPA was taken as the reference
molecule, XED force field was used to generate field points of KAPA
Fragment structure
(colored in black),
suggested by Dai et al., 2014 was aligned to KAPA
Cresset’s Spark program
was used to grow new
ligand by Bioisosteric substitution
Final structures of 3D
molecules were selected
based on field and shape
similarity relative to the
reference template
molecule KAPA. 4CXQ
active site was used as
the excluded volume to
penalize the steric
clashes.
Alignment scores ranged
from 0.54-0.62.
Positive
Negative
Hydrophobic
Shape
References
1. R. Dai, D. J. Wilson, T. W. Geders. et al. ChemBioChem. 2014, 15, 575.
2. S. Dey, J. M. Lane, R. E. Lee, E. J. Rubin, J.C. Sacchettini . Biochemistry. 2010, 49, 6746.
3. R. Dai, T. W. Geders, F. Liu. et al. J. Med. Chem. 2015, 58, 5208.
4. S. W. Park, D. E. Casalena, D. J. Wilson. et al. Chem. Biol. 2015, 22, 76.
Pharmacokinetics properties prediction of lead molecules by QikProp (Schrödinger, Inc., New York, NY, 2012)
2D-Diagram showing interaction of lead molecules in the active site of Mtb BioA
predicted by Glide docking program (Schrödinger, Inc., New York, NY, 2012) Glide energy (-59.70 kcal mol-1 to -42.35 kcal mol-1) and high GlideXP score (-11.32 kcal mol-1 and -9.38 kcal mol-1)
Cresset’s Forge program
was used to Field-based
alignment of structurally
diverse hit molecule obtained from Spark
3D molecular electrostatic potential (MEP)
Field Points
Radial plots help to
quickly visualize the
physical properties data
of molecules by
converting numerical
information into plots. It
provides trends, and sort
on overall fit to the
project profile or find
outliers enabling to
focus on the results.
ABA-3
ABA-30 ABA-100
ABA-101
ABA-601
SSM-7
ABA-603
ABA-602
ABA-600
ABA-604
Conclusion
1. Spark and Forge program (Cresset Bio Molecular Discovery Ltd., Cambridgeshire, UK, 2015) were used for linking chemistry.
scaffold replacement and Field-based alignment.
2. Final structures of 3D molecules were selected based on field and shape similarity relative to the reference template molecule KAPA.
3. Protein active site was used as the excluded volume to penalize the steric clashes.
4. A series of 300 molecules were designed and QikProp program (Schrödinger, Inc., New York, NY, 2012) was used to screen the
molecular dataset according to ADMET parameters.
5. Compounds with ADMET parameters in permissible ranges were docked in the active site of Mtb BioA using Glide program
(Schrödinger, Inc., New York, NY, 2012).
6. Compounds ABA series and SSM-7, having lowest Glide energy (-59.70 kcal mol-1 to -42.35 kcal mol-1) and high GlideXP score
(-11.32 kcal mol-1 and -9.38 kcal mol-1) showed good interactions with the active site of Mtb BioA.
7. These novel lead molecules designed by in silico approach could be viewed as potential Mtb BioA inhibitors.
