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Flashcards in Computers in Drug Design Deck (48):
1

spartan software: ______ software program for analyzing _________

representative/ small molecules

2

spartan software analyzes

atomic charges, thermodynamics, electrical, solvation and other properties

3

a molecular dynamics program measures ___________

the movement of each atom in a structure every femtosecond

4

define femtosecond

(1X10^-15)

5

molecular dynamics predicts the ___ of each atom at ______

energy/ each simulated orientation

6

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

"heating"/ introduce energy/ overcome "saddles"/ find lower energy conformation

7

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

in solution/ with its cellular target(s)

8

molecular modeling, compound only =

structural overlays

9

molecular modeling, compound and protein target =

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

10

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

true

11

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

false

12

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

13

molecular docking:

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

14

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

potential binding conformation (and biological activity)

15

True or False: molecular docking can be manual or automatic

true

16

molecular docking: rigid target and ligand:

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

17

molecular docking: rigid target/ flexible ligand

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

18

molecular docking: flexible target and ligand

very complicated, expensive

19

What is the first step in molecular docking?

Obtaining the crystal structure - co-crystal structure is important

20

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

true

21

in molecular docking, you identify the key interactions between:

ligand-protein and ligand-water molecules

22

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

potential high affinity binders/ binding energy analysis

23

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

synthesize and test it

24

how do you start de novo modeling?

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

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

design and build new ligands to fit into the binding site

26

you synthesize and test ________

low energy binders

27

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

de novo modeling

28

homology modeling:

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

29

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

true

30

name two secondary structures

alpha helix, beta sheets

31

name two tertiary structures

salt bridges, disulfide bonds

32

___________ is used to predict potential binding sites

homology modeling

33

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

homology modeling

34

how do you start homology modeling?

identify homologous proteins and determine sequence similarity

35

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

align the sequences/ structurally conserved/ structurally variable

36

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

37

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

refine and evaluate the unknown structure

38

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

39

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

flexible - allows for different binding conformations

40

when do you add rigidity to ligands?

second or third iterations

41

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

yes

42

define "in silico"

performed on a computer or via computer simulation

43

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

44

ligand-based screening types:

pharmacophore models and chemical similarity

45

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

46

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

docking-based screening

47

ligand-based screening - chemical similarity:

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

48

are computers utilized at all stages of drug development?

yes