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BACKGROUND
Increasing use of in silico drug screeningnarrowing
permutations
SCHRDINGER
Sources of error:
Not ab initio (pure QM) modeling
Software does not account for entropic and
S C H R D I N G E R ( W AT E R M A P ) T H E O R Y
S C H R D I N G E R ( W AT E R M A P ) T H E O R Y
Ligand disruption of hydration-site arrangement contributes
I N H O M O G E N O U S S O LV AT I O N T H E O R Y
Displacement of water molecules
(-kb2w)/(22) + gsw(r2,2)ln(gsww(r2,2)dr2d2 -
W AT E R M A P A L G O R I T H M P R O C E S S
Stage 1: Simulation
System is simulated for 2ns with full-explicit solvent
Heavy constraints applied on protein backbone, R
Stage 2: Clustering
Isolates hydration sites in region of interest then
C O N T I N O U S W AT E R M A P
Replace hydration-site model
Time-lapsed simulation
system
D R U G G A B I L I T Y: G L E E V E C / A B L
based on WaterMap
ideal drug-molecule
D R U G G A B I L I T Y: C O X - 2
hydration-sites, continuous
high free-energy density
D R U G G A B I L I T Y: P T P - 1 B
Example of an binding site
which is difficult/undruggable
D R U G D E S I G N & W AT E R M A P
G and H >> 0: Favorable to displace with drug
Methyl/halogens ideal for task (site often hydrophobic)
Explains many of the magic-methyl effects
H << 0 & G ~ 0: Favorable to replace with polar
A P P L I C AT I O N : S P I R O C Y C L I C S U L F A M I D E S I N
T R E AT M E N T O F A L Z H E I M E R S D I S E A S E
through BBB
A P P L I C AT I O N : S P I R O C Y C L I C S U L F A M I D E S I N
T R E AT M E N T O F A L Z H E I M E R S D I S E A S E
overlapping compound
(+4.94 kcal/mol)
W AT E R M A P : A N T I B I O T I C T R A N S L O C AT I O N
T H R O U G H P O R I N O M P C ( G R A M N E G AT I V E )
understood
concentrations
antibiotics
W AT E R M A P : A N T I B I O T I C T R A N S L O C AT I O N
T H R O U G H P O R I N O M P C ( G R A M N E G AT I V E )
W AT E R M A P : P 3 8 A M A P K I N A S E I N H I B I T O R S
W AT E R M A P : P 3 8 A M A P K I N A S E I N H I B I T O R S
inhibitor compounds
compounds
W AT E R M A P : P 3 8 A M A P K I N A S E I N H I B I T O R S
D R U G G A B I L I T Y: H I V P R O T E A S E
Catalytic Diad
unstable hydration-sites
W AT E R M A P L I M I TAT I O N S
Even with crystal structure, may not have explicit water
molecules
crystallization process)
W AT E R M A P A N D F U T U R E
Many promising results from studies utilizing WaterMap
Elucidated SARs of many ligands lacking binding
mechanism
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