Drug Design And Discovery Flashcards
1
Q
What is drug design based on
A
2
Q
Describe the drug discovery pathway
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3
Q
How are new hits identified
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4
Q
What are the limitations of HTS
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5
Q
What is CADD
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6
Q
What methods are used for CADD based on the structural information you have
A
7
Q
What is the CADD pathway
A
8
Q
What is LBDD
A
LBDD is a computational and experimental strategy where you start with known active compounds and use them to:
Predict new compounds with similar or improved activity.
Design new drug candidates by analyzing patterns in their structure and activity.
Since the target structure may be unknown, LBDD uses information from known ligands that bind to the target to guide drug design.
9
Q
What can LBDD methods be divided into
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10
Q
What is similarity searching
A
11
Q
What are the different molecular descriptors used for similarity measurements
A
12
Q
What is 2D fingerprint
A
13
Q
What is hashed fingerprint
A
Bit collision refers to a hash collision — when two different inputs produce the same hash output
14
Q
What is the tanimoto coefficient
A
15
Q
How is the tanimoto coefficient used
A
16
Q
What is scaffold hoping
A
It involves finding novel molecular structures (scaffolds) that are distinct from known compounds but still retain similar biological activity. This is often done by modifying or replacing certain parts of a known molecule (the “scaffold”) to create new compounds that might have improved properties, such as better binding affinity, selectivity, or pharmacokinetics.
17
Q
What is 3D fingerprinting
A
3D fingerprints encode information about the 3D spatial arrangement of atoms in a molecule. This includes factors such as the relative positions of atoms, their electrostatic properties, and the overall shape of the molecule.
18
Q
How is 3D shape search done
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19
Q
Why are 3D descriptors important
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20
Q
What is scoring
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21
Q
How are pharmacophores generated
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22
Q
What is meant by a 3 and 4 point model
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23
Q
How is a database search carried out
A
Pharmacophoric features in each ligandare
identified (Donors, acceptors, hydrophobic groups, etc)
• Ligands aligned so the corresponding features are
overlaid
• Conformational space explored
• Scoring system: number of features, goodness of fit to
features, conformational energy, volume of the overlay, etc
24
Q
What should a database search be compatible with
A
25
What is the roles of Thymidylate Synthase and
Dihydrofolate Reductase Enzymes
This function mThymidilate synthase maintains the dTMP pool, critical for DNA replication and repair. The enzyme has been of interest as a target for cancer chemotherapeutic agents.
26
What is QSAR
27
What are the three main methods of SBDD
28
What are the basic principles of SBDD
29
What is Virtual High Throughput Screening (vHTS)
30
What are the challenges of SBDD
31
Why do you want the crystal structure in SBDD
32
What are the different types of descriptors used in SBDD
33
What is SAR
34
What do you do once you have identified a compound in SBDD
35
What is lipinski’s rule of fives *
is a set of guidelines used in drug discovery to evaluate whether a chemical compound with a certain pharmacological or biological activity has properties that would make it likely to be an orally active drug in humans
No more than 5 hydrogen bond donors: (typically the sum of OHs and NHs)
No more than 10 hydrogen bond acceptors: (typically the sum of Ns and Os)
A molecular weight under 500 daltons
A log P (octanol-water partition coefficient) not greater than 5
36
What is the characteristics of virtual screening
Rigid docking:
•The ligand is treated as a rigid structure and only the
translational and rotational degrees of freedom are
considered
•Different ligand conformations
• each conformation is docked separately
•Protein is considered rigid
37
What is rigid docking
Rigid docking is a computational technique used in molecular docking where the structures of the receptor (typically a protein) and sometimes the ligand (a small molecule) are treated as fixed or rigid. In this approach, no conformational changes are allowed during the docking process, meaning that both the receptor and the ligand retain their original shapes
38
How is scoring done in SBDD
scoring functions are used to evaluate and rank how well a ligand binds to its target protein. These scoring methods aim to approximate the binding free energy and consider several key interaction components:
Physical and Chemical Interactions: Scoring functions estimate contributions from van der Waals forces, hydrogen bonding, electrostatic interactions, and sometimes even solvation/desolvation effects.
Empirical and Knowledge-Based Approaches: Some scoring functions are derived from experimental data, while others use statistical potentials based on known protein-ligand complexes.
Force Field Methods: These use principles from classical mechanics to calculate the energy of the system, often incorporating a detailed breakdown of interaction terms.
Ranking and Filtering: The computed scores allow researchers to rank a library of compounds to identify the most promising candidates for further study.
39
What is first principal scoring (SBDD)
calculates binding affinities based on fundamental physical principles, rather than relying on empirical data or statistical approximations
Uses molecular mechanics force fields (e.g., AMBER, CHARMM) to calculate potential energy contributions.
Accounts for van der Waals forces, electrostatics, hydrogen bonding, and solvation effects.
Advanced first-principles methods incorporate techniques like FEP and MD to estimate binding free energy by simulating molecular motion and interaction changes over time.
40
What is Empirical scoring (SBDD)
SBDD) involves using scoring functions that are derived by fitting to experimental data. These functions are designed to estimate binding affinities by combining different weighted terms that represent various types of molecular interactions
Empirical scoring functions use regression techniques on datasets of known protein-ligand complexes to assign weights to different interaction terms such as van der Waals forces, hydrogen bonding, electrostatic interactions, and desolvation effects.
41
What is flexible docking (SBDD)
Large protein conformational changes challenging for docking
Small conformational changes can be accommodated
42
What considerations need to be made before docking
Also need to consider :
Torsion angles provide flexibility to the ligand
• Rotatable bonds can be a problem
• Ring conformations (chair or boat)
43
What is Structure based fragment screening
(de novo)
Searching space of possible poses & conformations
(search algorithm)
• Orientation of molecule in binding site
• Predicting energetics of protein-ligand binding
(scoring function)
• Binding affinity
• Thermodynamics
Structure-based fragment screening (de novo) is an approach in drug discovery where the three-dimensional structure of a target protein is used to identify or design small, low-molecular-weight compounds—known as fragments—that can bind to specific regions of the protein. This strategy often involves building novel fragments from scratch (de novo) rather than starting with known ligands. Key aspects include:
Target-Driven Design: Utilizing structural information (from X-ray crystallography, NMR, or computational modeling) to pinpoint binding sites on the target protein.
Fragment Library Screening: Testing a library of small fragments that have diverse chemical features to see which ones bind to the target.
De Novo Design: In cases where no known binders exist, fragments can be designed de novo based on the shape and properties of the binding site.
Optimization Potential: Once initial binding fragments are identified, they can be further optimized or linked together to create more potent, drug-like molecules.
44
What can fragment evolution be used for *
Fragment evolution is a strategy used in fragment-based drug discovery to progressively optimize small, weakly binding chemical fragments into more potent and selective compounds. By iteratively modifying and elaborating on these fragments, researchers can:
Increase Binding Affinity: Add or modify functional groups to improve interactions with the target protein.
Enhance Selectivity: Tailor the fragment to engage more precisely with specific binding pockets, reducing off-target effects.
Optimize Drug-Like Properties: Adjust the chemical structure to improve solubility, stability, and overall pharmacokinetic profiles.
Expand Chemical Space: Explore new molecular scaffolds and interactions that might not be apparent from the initial fragment hits.
45
What can fragment linking be used for *
Fragment linking is a strategy in fragment-based drug discovery where two or more small chemical fragments that individually bind weakly to different parts of a target protein are chemically connected. This linking can lead to a new compound with a higher binding affinity and improved potency compared to the individual fragments. Specifically, fragment linking is used for:
Increasing Binding Affinity: By linking fragments, the resulting molecule can simultaneously engage multiple binding sites on the target, significantly boosting overall binding strength.
Enhancing Specificity: Properly designed linkers can help orient the fragments in a way that optimally fits the active site, leading to improved selectivity for the target protein.
Optimization of Lead Compounds: It serves as a method to merge initial fragment hits into a single, more drug-like lead candidate that may have better pharmacokinetic and pharmacodynamic properties.
Exploring New Chemical Space: This technique allows researchers to explore novel combinations of fragments that might not have been considered through traditional screening methods.
46
How can lead identification be done by fragment self assembly
Lead identification by fragment self-assembly involves using the target protein as a template to guide the spontaneous organization of small, weak-binding fragments into a larger, higher-affinity compound.
Template-Driven Assembly: The target protein’s binding site facilitates the correct orientation and proximity of complementary fragments, effectively “selecting” those that can interact synergistically.
Dynamic Combinatorial Chemistry: By allowing fragments to equilibrate in the presence of the target, the most energetically favorable combinations are stabilized. This dynamic process can reveal new lead compounds that form only when bound to the protein.
Rapid Exploration of Chemical Space: Instead of synthesizing and testing each potential compound individually, fragment self-assembly allows multiple fragments to combine and be evaluated in situ, speeding up the discovery process.
Optimization Starting Point: Once a self-assembled complex is identified, it provides a scaffold that can be further optimized for improved potency, selectivity, and drug-like properties.
47
How can lead progression be done by fragment optimisation
Lead progression by fragment optimization involves the systematic and iterative improvement of a fragment hit into a more potent and drug-like lead compound. This process builds on the initial fragment’s binding interactions with the target protein and refines them for better efficacy and pharmacological properties
Fragment Growth: Adding functional groups or chemical moieties to the original fragment to enhance interactions with additional regions of the target’s binding site.
Fragment Merging and Linking: Combining overlapping or adjacent fragment hits to create a single molecule that benefits from multiple binding interactions.
Structure-Guided Design: Using high-resolution structural information (e.g., X-ray crystallography or NMR) to guide modifications that improve binding affinity and specificity.
Iterative Optimization: Evaluating each modified compound for improvements in potency, selectivity, and drug-like properties, and then making further adjustments based on experimental and computational feedback.
ADME/T Optimization: Modifying the chemical structure to enhance pharmacokinetic and pharmacodynamic properties, such as solubility, metabolic stability, and bioavailability
48
What happens once hits have been identified (SBDD)
49
What other considerations are made when discovering a drug
50
How long does it take to discover a drug
51
What is meant by drug metabolism
the body chemically modifies drug molecules to change their structure, usually making them more water-soluble for easier elimination. These transformations are mainly carried out by enzymes, primarily in the liver
52
How are hydrophilic and lipophillic drugs metabolised
53
What pathway does orally administered drugs take
54
What influences the required dosage of a drug
55
What are the different phases of drug metabolism
56
What are phase I and II transformations
57
What happens in Phase I of metabolism
58
How is oxidation done
59
What is reduction
60
How can nitro phenols and carbonyls be reduced
61
What is meant by hydrolysis
62
What different ways can a functional group be introduced or unmasked in phase I
Oxidation
Reduction
Hydrolysis
63
What are the different oxidation enzymes , reduction enzymes, hydrolysis enzymes
64
Where does phase I occur and how
65
What is cytochrome P450
66
What is a main feature of cytochome P450
67
How does oxygen bind in cytochrome P450
68
Explain the cytochrome P450 cycle
69
Why does phase II occur
70
How can phase II of metabolism be carried out
71
What are the different metabolites produced by the metabolism of aspirin
72
What is glucuronidation
73
What is the name of the cofactor needed for glucoronidation and how is it produced
74
What is O- and N-glucoronidation
75
What if meant by sulfation
Sulfation is a Phase II metabolic reaction where a sulfate group (–SO₃⁻) is transferred to a drug or endogenous compound
76
What is acetylation and fatty acid conjugation
Fatty acid conjugation is a metabolic process in which a drug or endogenous compound is covalently linked to a fatty acid
77
What is meant by amino acid conjugation and glutathione conjugation
78
How can drugs be made more resistant to metabolism
How can drugs be made less resistant to metabolism
79
What do efflux transporters do
80
What are the factors that affect metabolism
81
What happens if drugs bind to plasma membrane proteins
82
What are prodrugs and how is their membrane permeability improved
Also improved by:
N methylation- N-demethylation is a common liver metabolic reaction, amines may be methylated to increase hydrophobicity. These N-methyl groups will be removed in the liver.
Membrane transporters-mimic substrate to cross membrane
Extend it’s life- 6-mercaptopurine is an immune suppressant
(organ transplants), but is eliminated from the body quickly. A prodrug that slowly is converted to the drug allows longer activity.
Less toxic or side effect- Salicylic acid is a painkiller, but phenolic -OH causes gastric bleeding. Aspirin has an ester to mask this toxic group until it is hydrolysed to salicylic acid so that it’s less toxic / has less side effects
83
Explain in more detail what a prodrug is
84
When designing a prodrug what properties needs to be considered
85
How are drugs characterised based on solubility and permeability
86
How do prodrugs pass through a membrane
87
What are the different types of prodrugs
88
What are the characteristics of an ideal drug carrier
89
What are Carrier linked prodrugs
90
What considerations are made when designing a prodrug
91
What is the most common prodrug form for alcohols and carboxylic acids
92
What is the general mechanism of esterases
93
How can alcohol containing drugs solubility be increased
Phosphate functional group for hydroxyl and amine
functionalities of poorly water-soluble drugs- enhance aqueous
solubility
– Very stable and easily converted to parent drug
• Carbonates and carbamates groups for carboxyl, hydroxyl or
amine functionalities
– more stable than the corresponding esters but are more
susceptible to hydrolysis than amides
94
How can prodrugs improve solubility and lipophilicity
95
How can absorption and distribution of a drug be improved
Carrier-mediated absorption - Prodrugs targeted towards specific membrane transporters are designed to have structural features that would allow them to be taken up by one of the endogenous transporters present at the intestinal epithelium. Targeting specific transporters for polar or charged drugs that have negligible passive absorption. Peptide transporters are attractive targets; widely distributed throughout the small intestine with sufficiently high transport capacity and broad substrate specificity
96
How can absorption and distribution of a drug be improved by Site-selective drug delivery
97
How can absorption and distribution of a drug be improved by Prolonged duration of drug action
98
What other ways can be used to improve absorption and distribution of a drug
99
What is a bipartite prodrug
100
Give an example of a bipartite drug
101
What is a tripartite prodrug
102
What is the mechanism of activation of a prodrug to the active drug
103
Give an example of a tripartite drug
104
What is a mutual prodrug
105
Give an example of a mutual tripartite prodrug
Sultamicillin is a mutual tripartite prodrug of the
antibiotic ampicillin and the β-lactamase
inhibitor, sulbactam
Improved pharmacokinetic properties.
Sultamicillin is more readily absorbed compared
to sulbactam.
Sultamicillin is broken down into ampicillin and
sulbactam in the body. β-lactamase producing
strains of bacteria are affected by the combined
effects of the antibiotic, ampicillin and the β-lactamase inhibitor, sulbactam
106
What are bioprecursors
107
What is sulfasalazine
108
What are Macromolecular drug carrier systems
109
What are the challenges with designing prodrugs
110
How can cancers be treated
111
What are Antibody–Drug Conjugates (ADCs)
112
Give some examples of ADCs
113
How do ADCs work
ADCs are designed to directly target and kill cancer cells, and so the antibody
has to be able to recognise and bind to its corresponding antigen localized on
the tumour cell.
• Once bound to the antigen, the entire antigen–ADC complex is then internalized through receptor-mediated endocytosis. The internalization process proceeds with the formation of a clathrin-coated early endosome
containing the ADC–antigen complex.
• Once inside the lysosome, the ADC is degraded and free cytotoxic payload
released into the cell, leading to cell death. The mechanism of cell death will
depend on the type of cytotoxic payload.
114
What is a crucial requirement of ADCs
115
What are the basic steps of designing an ADC
116
What are the challenges with designing ADCs
117
What are antibodies
118
What are the characteristics of light chain sequences of antibodies
119
What are the characteristics of antibody heavy chain sequences
120
What is an immunoglobulin fold
L & H chain folding to yield 3 CDR in each chain to
form walls of Ab binding groove
121
What are the different components of ADC linker design
122
How are antigens selected for ADC design
123
What should be considered with antibody drug linkers
124
What are cleavable linkers
125
What are the different types of cleavable linkers
126
What is meant by an acid labile linker
127
What is meant by a reducible linker
128
What is meant by an enzyme cleavable linker
129
What is an enzyme cleavable linker based on
130
What is the mode of action of enzyme cleavable linkers
131
What is meant by a non cleavable linker + characteristics
132
What is the mode of action of non cleavable linkers
133
How do you decide on the site of conjugation on ADCs
134
How does conjugation on an ADC via thiol groups work
135
What is the issue with thiol group conjugation
136
How is the issue with thiol group conjugation overcome
137
How does conjugation via Lysin residues work
138
What further strategies can be used to improve conjugation
139
Why is high cytotoxicity of ADCs needed
140
What are auristatins
141
What are Calicheamicins, Tubulysins, Duocarmycins, Benzodiazepines, Doxorubicin
142
What is the bystander effect
143
How does the bystander effect work
144
Where are the antibodies for ADCs obtained from
145
How can ADCs be used for breast cancer
