Structure-Guided Synthesis and Evaluation of Small-Molecule Inhibitors Targeting Protein–Protein Interactions of BRCA1 tBRCT Domain

Article abstract of DOI:10.1002/cmdc.201900300

The tandem BRCT domains (tBRCT) of BRCA1 engage phosphoserine-containing motifs in target proteins to propagate intracellular signals initiated by DNA damage, thereby controlling cell cycle arrest and DNA repair. Recently, we identified Bractoppin, the fi

Full text of DOI:10.1002/cmdc.201900300

Accepted Article
Title: Structure guided synthesis and evaluation of small molecule
inhibitors targeting protein-protein interactions of BRCA1 tBRCT
domain
Authors: Vadiraj Kurdekar, Saranya Giridharan, Jasti Subbarao,
Mamatha B Nijaguna, Jayaprakash Periasamy, Sanjana
Boggaram, Amol V Shivange, Gayathri Sadasivam,
Muralidhara Padigaru, Vijay Potluri, Ashok R Venkitaraman,
and Kavitha Bharatham
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: ChemMedChem 10.1002/cmdc.201900300
Link to VoR: http://dx.doi.org/10.1002/cmdc.201900300
A Journal of
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ChemMedChem
10.1002/cmdc.201900300
Supplementary data
Table S1. Thermodynamic properties of most stable water molecules
observed by GIST analysis
Water grouping (red sphere) based on high density and with greater free
energy change.
ID
ΔEsw
ΔEww
ΔEtotal
TΔStrans TΔSorient TΔStotal
ΔG
w1
w2
w3
w4
w5
w6
w7
w8
w9
-14.28
-2.33
-16.61
-2.176
-3.586
-1.575
-7.862
-4.490
-8.460
-5.137
-1.679
-2.540
-0.284
-0.580
-0.185
-1.600
-0.559
-1.029
-0.689
-0.166
-1.757
-2.290 -4.830 -11.779
-1.105 -1.071
-2.473 -1.113
-0.959 -0.616
-3.828 -4.034
-2.880 -1.610
-5.997 -2.463
-3.622 -1.515
-1.392 -0.287
-0.183 -0.467
-0.304 -0.884
-0.122 -0.306
-0.924 -2.524
-0.303 -0.862
-0.605 -1.634
-0.548 -1.236
-0.131 -0.298
-1.601 -3.359
-1.708
-2.702
-1.269
-5.338
-3.629
-6.827
-3.901
-1.382
-9.361
w10 -11.373 -1.346 -12.719
All values are in Kcal/mol unit
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ChemMedChem
10.1002/cmdc.201900300
Figure S1. Stability of Bractoppin’s Binding mode evaluated in three 20 ns MD
simulations: A) The histogram shows the fraction of protein- ligand contacts
between Bractoppin and BRCA1 pocket residues plotted on X-axis tBRCT during
MD simulations, and the interaction fraction plotted on Y-axis for the three
repeats. B) Calpha atom Root Mean Square Deviation (RMSD) of BRCA1 tBRCT
domain residues.
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ChemMedChem
10.1002/cmdc.201900300
Protein as excluded volume
Spark –R group exploration
For electrostatic similarity
Point of
attachment
CCBT002
scaffold
Field score cutoff >0.9
Aromatic ring
electrostatics
Water
electrostatics
Glide-SP docking
refine only
Glide-SP docking
flexible
R group search for parent compound
CCBT002
Similar interaction and pose
in both docking
1.
Using replaceable water
identified by GIST calculations)
(
electrostatics
Access Synthetic feasibility
by Medicinal Chemist
2.
Using ring electrostatics from
structure based studies
Figure S2: Work-flow for R group search using Spark-cresset tools. Required
electrostatic field point of R group to attach on CCBT002 scaffold were identified
by water thermodynamic analysis and structural analysis. New Spark suggestions
were further filtered by docking and finally shortlisted based on synthetic
feasibility while accounting for time, cost and novelty involved in synthesis.
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