cadd Flashcards
general use of computers from hit generation to lead optimization
Computer-aided drug design (CADD)
Computer-aided drug design (CADD) is the general use of computers from ___________ to ________
hit generation; lead optimization
specific use of computers
when still filtering out massive amounts of chemicals
Virtual screening
T/F: CADD is omplementary to biological (in vitro/ in vivo) screening to reduce uncertainty in finding promising molecules
True
In drug discovery, the common goal at the molecular level is binding of the __________ and the _________
ligand; drug target
The main players in CADD should be the _______
and the __________
ligand; drug target
Ligand-based drug design (LBDD) is based entirely on the _______________
hit/lead compounds
Done in the absence of data for the drug target
Ligand-based drug design (LBDD)
T/F: LBDD does not requires similar compounds that work already
exist
False; requires
Where are drug molecules studied
Ligand-based drug design (LBDD)
You already know the information about the drug
molecules, receptor, and the drug target
Structure-based drug design (SBDD)
T/F: SBDD is done in the presence of the drug target
true
SBDD is based on _________________ between the
drug target and the hits/leads
measuring interactions
CADD OUTLINE
● Preparing the ligand
● Ligand-based Drug Design (LBDD)
● Receptor modelling
● Structure-based Drug Design (SBDD)
PREPARING THE LIGAND includes
DRAWING THE MOLECULE
ENERGY MINIMIZATION
Various software packages are available which can be used to construct molecules quickly to professional standard
DRAWING THE MOLECULE
T/F: you can place atoms freely but can end up with a weird result
true
T/F: you just need to enter a code and the program auto-draws it properly
True
pertains to a certain code so the program can provide the 3D structure
SMILES
Free-style drawing programs allow a person to make unrealistic molecular models
ENERGY MINIMIZATION
T/F: Unrealistic models can’t predict anything properly
True
Unrealistic = _____________
high energy
___________ makes non-ideal bonds, angles, and
other geometries more realistic
Minimization
Minimizaion is usually carried out by a __________ which corrects everything automatically
molecular mechanics
program
LBDD includes
SIMILARITY SEARCHES
QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP (2D QSAR)
PHARMACOPHORE MODELLING
Similarity property principle (SPP):
Similar compounds should have similar properties
Easiest way for a beginner to understand structure-activity relationships in medicinal chemistry
Similarity searches
T/F: Similarity is avoided by companies due to intellectual property rights and patents
True
phenomenon where a very slight change in two similar-structured compounds spell a night-and-day difference in their activity
Activity cliff
CBZ, Amitriptyline, Loratadine have the same parent compound: _____________ but they differ on the substituents
dihydro dibenzo annulene
CBZ or Carbamazepine is an ____________
anticonvulsant
Amitriptyline is an ___________
antidepressant
Loratadine is an ____________.
antihistamine
T/F: Similarity is quite subjective
True
T/F: Assumptions on similar compounds can be
made by the best medicinal chemists in the world and still be proven wrong when experiments prove unexpected activity cliffs
True
attempts to make similarity judgments more objective
Similarity coefficients
examples of similarity coefficient
Tanimoto (Tc), Tversky (Tv), and Dice coefficients (Dc)
most common similarity coefficient
Tanimoto
In _____________, the coefficient should be computed based on the similarity of the constituents present in the particular compound.
Tanimoto
T/F: coefficients can distinguish similarity relationships in a consistent manner
True
The higher the tanimoto coefficient = the _____________ the similarity
higher
An alternative to similarity coefficients
structure overlay
Root mean square distance (RMSD) measures how “___________” all the atoms are
different
lower RMSD = ________ similar and ________
reliable
more;more
In structure overlay it is important that molecules are already in ______________ (active/inactive) conformation since molecules are assumed to be rigid
active
Good with rigidity:
Less calculation time
Bad with rigidity:
Less realistic (molecules
constantly move!)
Attempts to convert physicochemical properties of a
potentially active molecule into plots or equations
QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP (2D QSAR
Physicochemical properties:
partition coefficient,
solubility, polarity, etc.
By quantifying physicochemical properties, it should
be possible to “________” if a compound is active or
not
estimate
T/F: QSAR is done in wet lab
False: QSAR is strictly computational/dry lab
QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP (2D QSAR) is used to compare actual activity and phase predicted
activity of a test compound through _________
linear regression method
F/T: QSAR is often done at the start of a project
True
f a screening molecule does not fit a QSAR equation/plot, it implies that it is (active/not active)
not active
direct biological activity is used for computation; harder to interpret
Free-Wilson Approach
A ‘flow diagram’ which allows initial QSAR for a
small number of compounds
Topliss Scheme
Used when compounds are too few for a reliable
Hansch equation
Topliss Scheme
A plot where the y-axis is σ (EWG/EDG power) and the x-axis is π (hydrophobicity).
Craig Plot
Useful in planning which should be used in a
QSAR study
Craig Plot
allows the medicinal chemist to identify substituents which may be potential substitutions/ bioisosteres for synthesis
Knowledge of QSAR-derived constants
QSAR properties
Hydrophobicity
Electronic Effects
Steric Factors
Often measured by the partition coefficient (P) or more often, its logarithm (logP)
Hydrophobicity
relationship of partition coefficient, nonpolarity, hydrophobicity, metabolism, activity
directly proportional
measure of how hydrophobic a substituent is relative to hydrogen
Substituent hydrophobicity constant (π)
A _____________ (postive/negative) value of π indicates that the substituent is more hydrophobic than hydrogen
positive
T/F π values for aromatic substituents are different from those used for aliphatic substituents
True
measure of the electron withdrawing or electron-donating ability of a substituent
Hammett substituent constant (σ)
Electron withdrawing substituents/
groups (EWG
Cl, Br, halogens, ketone,
aldehyde, carboxylic acid, carbonyl
(-) Electron-donating substituents/ groups (EDG):
Methyl (CH3), OH, NH3
T/F; Electronic effects are Based on probability of hydrolysis
True
A bulky substituent may act like a shield and hinder the ideal interaction between a drug and its binding site
Steric Factors
a bulky substituent may help to orientate a drug properly for ____________ (maximum/minimum) binding and ___________ (increase/decrease) activity
maximum; increase
portion/regions of a drug molecule that gives it its activity
Pharmacophore
“Face” of the molecule that interacts with the
receptor
Pharmacophore
pharmacophore
of most Cell Wall Synthesis Inhibitor (CWSI) antibiotics (Penicillin, Carbapenem, Cephalosporin)
β-lactam ring
T/F: pharmacophore is a specific compound or functional group
False; it is not
Pharmacophores are __________, polygon-like figures where points represent features that a hit compound must satisfy
abstract
Pharmacophore is usually __________ based and is using almost similar compound
ligand
When finding a new pharmacophore, it is required that the actives are already rigid in their ___________ (inactive/active) conformation
active
If there are multiple active compounds, their conformations can be assessed to determine the ____________ (or “centers”) their substituents occupy
common spaces
When those centers are identified across compounds, the program forms the final ligand-based pharmacophore model a.k.a. _____________-
pharmacophore hypothesis
T/F: The centers must have defined IMFs
true
T/F: Sometimes the model doesn’t connect those
points, but the points are enlarged to visible spheres
or arrows
True
Receptor modelling include
XRC
Homology modelling
Used for various materials in the crystallized state to determine the arrangement of atoms within a crystal
XRC
XRC
is a __________ method – you need a real protein
sample and a real X-ray generator
biophysical
Receptors models from XRC are often definitive and
best for ________
SBDD
T/F: XRC can also be used to determine active conformations,
and consequently, pharmacophores
True
The main problem of XRC is that many proteins are
hard to crystallize
same name, different organisms
Homolog
T/F: Human and bacterial hexokinase are homologs
True
using X-ray structures from other organisms’ proteins to create your own protein
Homology modelling
Homology modelling is done whenever there is no __________ yet of
the protein in the target organism
X-ray structure
Homology remodelling requires
■ crystal structure of a homolog (template)
■ protein sequence from target organism
(copies the template structure)
Steps in homology remodelling
1) identify primary model
2) Identify sequence identity thru sequence allignment
3) model refinement
T/F: Homology remodelling suffers from multiple error sources
true
STRUCTURE-BASED DRUG DESIGN includes
Molecular docking
Molecular dynamics simulation
Fragment based drug design
De Novo Drug Design
T/F: Under SBDD, IMFs are not anymore assumptions but real interactions between drug and receptor
True
convert energy values from the said IMFs into “scores” that correspond to how good a molecule can affect the target or not
SBDD programs
Lesser energy = _________ (better/worse_ drawing of the structure
better
T/F: Shape is still included in the SBDD.
False; Shape is no longer included in the SBDD.
Involves “docking” or fitting the ligand to the target/receptor
Molecular docking
T/F: Molecular docking does not need known actives
True
The calculations required for docking and scoring have to be ________ in order to process the number of molecules
rapid
most commonly done type of dockin
Style 1
essentially what we call molecular
dynamics
Style 3
identified through X-ray crystallography, homology modelling, and
NMR
Protein data bank (PDB)
T/F: Good docking programs should have a good scoring system, rewarding higher scores for better potential ligands (and vice-versa)
True
Main hurdles for docking:
-interference of water molecules
-protein flexibility
- flexible
ligands
esigned to mimic the movement of atoms within a molecule or complex
Molecular dynamics
T/F: MD simulations prove or disprove uncertainties that docking (by virtue of being stationary) can never answer
True
Programs that perform MD use “__________” which are collections of mathematical formulas that try to make MD simulations as realistic as possible
force fields
__________ pertain to the “algorithms developed by countless mathematicians and physicians” mentioned earlier
force fields
T/F: MD Has to be realistic, so even temperature, pressure, ion concentration, etc. should be consistent and recorded
True
T/F: In MD, The person running the simulation has controls over
literally everything
True
Uses docking or dynamics on “fragments” of a ligand instead of complete molecules
FRAGMENT BASED DRUG DESIGN
Fragment based drug design starts with the ___________, then more flexible
“fragments” are added layer per layer
rigid part (anchor)
T/F: fragments may be tailor-fitted for different receptors
True
Pilot test; virtual screening
DE NOVO DRUG DESIGN
Ligand structure is _______; protein structure is
________
unknown; known
De novo drug design disadvatage
There is a lack of related study which
makes it prone to certain errors.
De novo drug design focuses on
proof of concept based on the new fresh
idea
In Denovo drug design, the novelty of the structures obtained is limited to
the operator’s own ___________ and ________
imagination and originality
the real strength in de novo drug design is that
can stimulate new ideas and identify novel lead
structures
De novo is Very experimental and arbitrary
