Computers in Drug Design Flashcards
spartan software: ______ software program for analyzing _________
representative/ small molecules
spartan software analyzes
atomic charges, thermodynamics, electrical, solvation and other properties
a molecular dynamics program measures ___________
the movement of each atom in a structure every femtosecond
define femtosecond
(1X10^-15)
molecular dynamics predicts the ___ of each atom at ______
energy/ each simulated orientation
molecular dynamics allows for ____ a molecule to _____________ to ______ and ______
“heating”/ introduce energy/ overcome “saddles”/ find lower energy conformation
molecular modeling describes and predicts how a compound interacts ______ and _______
in solution/ with its cellular target(s)
molecular modeling, compound only =
structural overlays
molecular modeling, compound and protein target =
molecular docking (SBDD), de novo modeling and homology modeling
True or False: molecular modeling software generates numerous potential structural overlays
true
True or False: molecular modeling software identifies the most likely correct overlay
false
molecular modeling structural overlays are most often used to
1) identify pharmacophore for a series of analogues 2) predict binding conformation of a new series of analogues
molecular docking:
fitting a drug or potential drug into a known binding site and analyzing interactions
molecular docking can predict ____ of new compounds before synthesis and evaluation
potential binding conformation (and biological activity)
True or False: molecular docking can be manual or automatic
true
molecular docking: rigid target and ligand:
simplest and quickest, you need to know the active conformation of ligand
molecular docking: rigid target/ flexible ligand
more complex, you don’t need to know the active conformation of the ligand
molecular docking: flexible target and ligand
very complicated, expensive
What is the first step in molecular docking?
Obtaining the crystal structure - co-crystal structure is important
True or false: in molecular docking you identify the amino acids lining the binding site
true
in molecular docking, you identify the key interactions between:
ligand-protein and ligand-water molecules
in molecular docking, after docking a new compound into the binding site, you identify _________ by _________
potential high affinity binders/ binding energy analysis
what do you do after you identify a new lead compound through molecular docking?
synthesize and test it
how do you start de novo modeling?
get crystal and co-crystal structure (of ligand in binding site)
in de novo modeling, you identify the binding site, the amino acids lining the binding site, other binding regions in the binding site, and then you
design and build new ligands to fit into the binding site
you synthesize and test ________
low energy binders
what can you use to get a lead compound for SBDD?
de novo modeling
homology modeling:
create a three-dimensional model of an unknown protein based on amino acid sequence similarity with a protein of known 3D structure
true or false: the majority of different amino acid sequences adopt a relatively small number of structures
true
name two secondary structures
alpha helix, beta sheets
name two tertiary structures
salt bridges, disulfide bonds
___________ is used to predict potential binding sites
homology modeling
__________ is used with standard modeling procedures to dock compounds in binding site
homology modeling
how do you start homology modeling?
identify homologous proteins and determine sequence similarity
after you find homologous proteins for homology modeling and determine sequence similarity, you _____ and identify ______ and _________ regions.
align the sequences/ structurally conserved/ structurally variable
in homology modeling, you generate _____ for structurally conserved residues of the unknown structure and _________ for the structurally variable regions in the unknown structure
coordinates/ conformations
after you build the side-chain conformations in homology modeling, you
refine and evaluate the unknown structure
why should you not design structures that completely fill the binding pocket?
space for future optimization is needed, space allows for different binding conformations than predicted
are rigid or flexible newly designed ligands preferred for molecular modeling/ docking?
flexible - allows for different binding conformations
when do you add rigidity to ligands?
second or third iterations
should the binding conformation of a ligand be a stable conformation?
yes
define “in silico”
performed on a computer or via computer simulation
docking based screening
virtual libraries are docked into a known receptor or enzyme binding site and scored for their potential ability to bind with high affinity
ligand-based screening types:
pharmacophore models and chemical similarity
ligand-based screening - pharmacophore models:
compounds known to bind in the same site on a receptor or enzyme are used to build a model of the binding site
what is a ligand-based screening pharmacophore model used for?
docking-based screening
ligand-based screening - chemical similarity:
lead compound is compared to structure databases to identify other molecular structures with similar pharmacophoric and physicochemical elements
are computers utilized at all stages of drug development?
yes
