Computers in Drug Design

Question 1

spartan software: ______ software program for analyzing _________

Answer 1

representative/ small molecules

Question 2

spartan software analyzes

Answer 2

atomic charges, thermodynamics, electrical, solvation and other properties

Question 3

a molecular dynamics program measures ___________

Answer 3

the movement of each atom in a structure every femtosecond

Question 4

define femtosecond

Answer 4

(1X10^-15)

Question 5

molecular dynamics predicts the ___ of each atom at ______

Answer 5

energy/ each simulated orientation

Question 6

molecular dynamics allows for ____ a molecule to _____________ to ______ and ______

Answer 6

“heating”/ introduce energy/ overcome “saddles”/ find lower energy conformation

Question 7

molecular modeling describes and predicts how a compound interacts ______ and _______

Answer 7

in solution/ with its cellular target(s)

Question 8

molecular modeling, compound only =

Answer 8

structural overlays

Question 9

molecular modeling, compound and protein target =

Answer 9

molecular docking (SBDD), de novo modeling and homology modeling

Question 10

True or False: molecular modeling software generates numerous potential structural overlays

Answer 10

true

Question 11

True or False: molecular modeling software identifies the most likely correct overlay

Answer 11

false

Question 12

molecular modeling structural overlays are most often used to

Answer 12

1) identify pharmacophore for a series of analogues 2) predict binding conformation of a new series of analogues

Question 13

molecular docking:

Answer 13

fitting a drug or potential drug into a known binding site and analyzing interactions

Question 14

molecular docking can predict ____ of new compounds before synthesis and evaluation

Answer 14

potential binding conformation (and biological activity)

Question 15

True or False: molecular docking can be manual or automatic

Answer 15

true

Question 16

molecular docking: rigid target and ligand:

Answer 16

simplest and quickest, you need to know the active conformation of ligand

Question 17

molecular docking: rigid target/ flexible ligand

Answer 17

more complex, you don’t need to know the active conformation of the ligand

Question 18

molecular docking: flexible target and ligand

Answer 18

very complicated, expensive

Question 19

What is the first step in molecular docking?

Answer 19

Obtaining the crystal structure - co-crystal structure is important

Question 20

True or false: in molecular docking you identify the amino acids lining the binding site

Answer 20

true

Question 21

in molecular docking, you identify the key interactions between:

Answer 21

ligand-protein and ligand-water molecules

Question 22

in molecular docking, after docking a new compound into the binding site, you identify _________ by _________

Answer 22

potential high affinity binders/ binding energy analysis

Question 23

what do you do after you identify a new lead compound through molecular docking?

Answer 23

synthesize and test it

Question 24

how do you start de novo modeling?

Answer 24

get crystal and co-crystal structure (of ligand in binding site)

Question 25

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

Answer 25

design and build new ligands to fit into the binding site

Question 26

you synthesize and test ________

Answer 26

low energy binders

Question 27

what can you use to get a lead compound for SBDD?

Answer 27

de novo modeling

Question 28

homology modeling:

Answer 28

create a three-dimensional model of an unknown protein based on amino acid sequence similarity with a protein of known 3D structure

Question 29

true or false: the majority of different amino acid sequences adopt a relatively small number of structures

Answer 29

true

Question 30

name two secondary structures

Answer 30

alpha helix, beta sheets

Question 31

name two tertiary structures

Answer 31

salt bridges, disulfide bonds

Question 32

___________ is used to predict potential binding sites

Answer 32

homology modeling

Question 33

__________ is used with standard modeling procedures to dock compounds in binding site

Answer 33

homology modeling

Question 34

how do you start homology modeling?

Answer 34

identify homologous proteins and determine sequence similarity

Question 35

after you find homologous proteins for homology modeling and determine sequence similarity, you _____ and identify ______ and _________ regions.

Answer 35

align the sequences/ structurally conserved/ structurally variable

Question 36

in homology modeling, you generate _____ for structurally conserved residues of the unknown structure and _________ for the structurally variable regions in the unknown structure

Answer 36

coordinates/ conformations

Question 37

after you build the side-chain conformations in homology modeling, you

Answer 37

refine and evaluate the unknown structure

Question 38

why should you not design structures that completely fill the binding pocket?

Answer 38

space for future optimization is needed, space allows for different binding conformations than predicted

Question 39

are rigid or flexible newly designed ligands preferred for molecular modeling/ docking?

Answer 39

flexible - allows for different binding conformations

Question 40

when do you add rigidity to ligands?

Answer 40

second or third iterations

Question 41

should the binding conformation of a ligand be a stable conformation?

Answer 41

yes

Question 42

define "in silico"

Answer 42

performed on a computer or via computer simulation

Question 43

docking based screening

Answer 43

virtual libraries are docked into a known receptor or enzyme binding site and scored for their potential ability to bind with high affinity

Question 44

ligand-based screening types:

Answer 44

pharmacophore models and chemical similarity

Question 45

ligand-based screening - pharmacophore models:

Answer 45

compounds known to bind in the same site on a receptor or enzyme are used to build a model of the binding site

Question 46

what is a ligand-based screening pharmacophore model used for?

Answer 46

docking-based screening

Question 47

ligand-based screening - chemical similarity:

Answer 47

lead compound is compared to structure databases to identify other molecular structures with similar pharmacophoric and physicochemical elements

Question 48

are computers utilized at all stages of drug development?

Answer 48

yes