lecture 7 Flashcards
what part of drug development is HTS, LBDD and SBDD part of?
stage 1 drug discovery
* lead identification*
what are examples of omics technologies?
genome
epigenome
transcriptome
proteome
metabiome
what is epigenetics?
study of how environment & lifestyle change how genes are expressed
how does epigenetics work?
dna methylation— adds methyl groups to DNA
histone modification–histone tail mods can affect interactions between DNA and histones
non coding RNA-associated w gene silencing
what can we use in HTS?
—-chemical libraries— tested w whole cells or purified enzymes
—-virtual— in silica funneling of large libraries to predict hits ( can be ligand or structure based)
what is needed for virtual screening Ligand based screening?
Structure based?
chemical similarity, pharmacophore,
QSAR,
machine learning
molecular docking + scoring
what can we use in experimental protein structure determination?
x ray crystallography – for active site
cryo- electron microscopy (cryo-EM)— atomic resolution
nuclear magnetic resonance (NMR)– good for protein dynamics
what is levinthal’s paradox?
–proteins fold into lowest energy state in seconds
–searching for entire landscape of conformations is not possible in short timeframe
–degrees of freedom increase exponentially with # of residues
what does molecular dynamics use?
physics equations for:
bond,
angle,
dihedral,
improper,
vander waals, electrostatic
what happens at each of these timescales in protein motion?
0.1-1
1-10
10-100
1-10ns
10-100ns
–HB vibrations
–HB breaking, rotation relax, translational diffusion
-water dipole relaxation
-side chain fluctuations
–protein tumbling
–conformational transitions
what are the levels of theories and spatiotemporal?
atomic:
Ab initio DFT
RexFF MD
Classical MD
Coarse grained MD,MC
multiphyiscs
continuum theory
macroscale
what is an example of bottom up and town down?
classical MD —> coarse grained
coarse grained–> classical
what does rosetta coarse grained use?
physics + data
how does rosetta de novo protocol work?
use primary sequence to predict secondary structure
generate libraries
Monte Carlo fragments insertions
evaluate energy model
low resolution model–> relax backbone–> final model
what are remaining challenges in protein folding?
dynamics
point mutations
protein complexes
transmembrane proteins
interactions with non
proteogenic molecules
what was FDA first HIV integrate inhibitor, found by protein dynamics?
raltegravir
what are the components of molecular docking?
search algorithm (molecular dynamics)
+
scoring function (knowledge based)
—->docking assessment
what is most accurate in optimizing hit to lead?
what does it use?
quantum mechanics
uses Schrodinger equation
what does rosetta fold (alpha fold 3) all atom use?
***ML based
proteins,
nucleic acids,
metal
small molecule
covalently mod residues
what uses score based vs ML based?
Rosetta, autodock, Schrödinger Glide, DOCK, MOE
Diffdock, Roseall atom, alphafold 3
