Exam II HW/Quiz Review

Question 1

From a computational perspective, what is one of the primary reasons that simulating protein folding is challenging?

Answer 1

The vast number of rotatable bonds in a protein creates an enormous conformational space, making it computationally intensive to explore all possible folding configurations.

Question 2

From a molecular viewpoint, what would be a reasonable functional role for an amphipathic alpha helix in a protein?

Answer 2

An amphipathic alpha helix can mediate interactions with both hydrophobic and hydrophilic environments—such as anchoring proteins to membrane interfaces—because one face interacts with nonpolar lipid tails while the other interacts with the aqueous environment.

Question 3

Which of the following statements best describes protein quaternary structure?

Answer 3

Protein quaternary structure involves the association of multiple polypeptide chains into a functional protein complex, which can be homomeric (identical subunits) or heteromeric (different subunits).

Question 4

Which of the following statements best defines the protein primary structure?

Answer 4

Protein primary structure is defined by the linear sequence of amino acids that form the common peptide backbone with variable side chains.

Question 5

Which of the following best distinguishes the hydrogen bonding patterns in alpha helices from those in beta sheets?

Answer 5

In alpha helices, hydrogen bonds form between the carbonyl oxygen of one amino acid and the amide hydrogen of an amino acid four residues ahead in the sequence, whereas in beta sheets, hydrogen bonds form between backbone groups of amino acids that are distant in the primary sequence but align side-by-side.

Question 6

What is the primary reason why protein-protein interactions are generally harder to inhibit with small molecules compared to enzymes with small-molecule substrates?

Answer 6

Protein-protein interactions usually involve large, flat surfaces rather than well-defined pockets.

Question 7

Why is computer-aided drug discovery (CADD) valuable in the drug development process?

Answer 7

CADD helps prioritize compounds for experimental testing, reducing time and cost.

Question 8

What is the main reason why metabolite analogs are useful in drug development?

Answer 8

They mimic natural molecules but are modified to alter their biological effect.

Question 9

Why might a drug discovered through phenotypic screening be more difficult to optimize than one identified via receptor-centric screening?

Answer 9

Phenotypic screening identifies compounds based on cellular or tissue-level effects, but the precise molecular target may be unknown, complicating optimization.

Question 10

How does entropy affect the binding of a small-molecule ligand to a protein target?

Answer 10

Binding typically reduces the ligand’s conformational freedom, leading to an unfavorable entropic penalty that must be offset by strong interactions.

Question 11

Which of the following statements best describes how ligand binding affinity is determined?

Answer 11

Ligand binding affinity is quantified by the dissociation constant (Kd), which is calculated as koff/kon.

Question 12

What is a key advantage of designing allosteric drugs compared to orthosteric drugs?

Answer 12

Allosteric drugs can provide more selective targeting when a protein’s orthosteric site binds a common endogenous ligand.

Question 13

Which of the following best describes the “population shift” or “conformational selection” model of ligand binding?

Answer 13

The receptor exists in multiple low-energy conformational states, and the ligand binds to a pre-existing state, shifting the population toward that conformation.

Question 14

What is a key factor that limits the maximum possible (fastest) association rate constant (kon) for ligand binding?

Answer 14

The maximum kon is limited by the rate at which molecules diffuse through water to reach the target.

Question 15

What is a key advantage of orthosteric drugs compared to allosteric drugs?

Answer 15

Orthosteric drugs directly compete with endogenous ligands, making them more likely to fully block protein activity.

Question 16

Which of the following is an advantage of using the SMILES representation for chemical structures?

Answer 16

SMILES provides a simple text-based representation of molecular structures, making it easy to store and share chemical data.

Question 17

Which of the following is a key limitation of SMILES compared to other molecular file formats?

Answer 17

SMILES does not store 3D atomic coordinates, limiting its ability to represent molecular conformations.

Question 18

What is the primary advantage of canonical SMILES compared to regular SMILES representations?

Answer 18

Canonical SMILES ensures a unique representation for a given molecule, making it useful for database indexing and comparison.

Question 19

What is a key difference between SDF files and SMILES representations?

Answer 19

SDF files can store 3D atomic coordinates, while SMILES only encodes molecular connectivity.

Question 20

What is a key advantage of using PubChem as a molecular database?

Answer 20

PubChem integrates both chemical and biological data, allowing users to explore molecular structures and their biological activities.

Question 21

What is one of the primary uses of DrugBank in cheminformatics and drug discovery?

Answer 21

DrugBank links chemical drug data with biological drug targets, making it useful for understanding drug mechanisms.

Question 22

Suppose two molecules have the following fingerprints:

mol1 = 0101100010
mol2 = 1001100011

What is the Tanimoto similarity between these two fingerprints?

Answer 22

0.5

Question 23

What is the purpose of using the Butina algorithm in the context of molecular library design?

Answer 23

The Butina algorithm helps create diversity sets by removing highly similar molecules and retaining unique cluster “centroids.”

Question 24

Why are Pan Assay Interference Compounds (PAINS) problematic in drug discovery?

Answer 24

PAINS often produce false positives in high-throughput screening due to nonspecific interactions.

Question 25

What is the primary reason Lipinski’s Rule of Fives is used in drug discovery?

Answer 25

helps identify drug-like compounds that are more likely to have good oral bioavailability.

Question 26

What is the main advantage of using molecular fingerprints, such as MACCS keys, for chemical similarity searches?

Answer 26

Molecular fingerprints allow for rapid comparison of chemical structures by representing molecules as binary vectors.

Question 27

Given the following binary fingerprints for two molecules: Molecule A: [1, 0, 1, 1, 0, 1, 0, 0] Molecule B: [1, 1, 0, 1, 0, 1, 1, 0] Calculate the Tanimoto coefficient for these molecules.

Answer 27

0.5

Question 28

Which of the following best describes a key limitation of phenotypic screening in the drug discovery process?

Answer 28

Phenotypic screening does not provide information on the mechanism of action or the specific target of a compound. This limitation means that while the screening can identify compounds that produce a desired biological effect, it does not clarify why the compound is active or pinpoint its target.

Question 29

Why is the process of developing a new drug both expensive and time-consuming?

Answer 29

The drug development process involves multiple stages, including target identification, preclinical testing, clinical trials, and regulatory approval, all of which require significant time and financial investment.

Question 30

Why are bioassays important in the drug discovery process?

Answer 30

Bioassays help evaluate the biological activity and potency of compounds, allowing researchers to determine their potential as drug candidates. Bioassays are essential for screening compound libraries to identify molecules with desired biological effects, as well as for assessing the strength (potency) of these effects.

Question 31

What is a key challenge of using natural products for drug development?

Answer 31

Natural products can be difficult to identify, isolate, and manufacture at scale, making drug development costly and complex.

Question 32

Which of the following best summarizes Gypsum-DL’s approach to converting 2D molecular representations into accurate 3D models for virtual screening?

Answer 32

Incorporating multiple molecular variants—such as different ionization, tautomeric, stereochemical, cis/trans, and ring-conformational states—while using clustering and energy evaluation to manage the number of models.

Question 33

Based on the reading, what is an important consideration when selecting software tools for preparing small-molecule libraries for virtual screening?

Answer 33

Licensing restrictions and cost considerations can hinder long‐term accessibility and the free distribution of screening workflows.

Question 34

Why is it critical to enumerate multiple molecular forms (e.g., different ionization, tautomeric, and ring conformations) when preparing small-molecule libraries for virtual screening?

Answer 34

Different molecular forms can be stabilized by protein binding pockets, thereby affecting binding affinity predictions.

Question 35

Why is sampling alternate ring conformations important when preparing small-molecule libraries for virtual screening?

Answer 35

It accounts for the fact that alternate ring conformations adopt different spatial arrangements that influence how a molecule fits into a protein pocket.

Question 36

Why is the desalting step critical in the preparation of small-molecule libraries for virtual screening?

Answer 36

Desalting removes extraneous counterions and salts that do not contribute to the molecule’s binding, ensuring that only the relevant fragment is used. Counterions may interfere with docking simulations, so keeping only the primary compound improves model accuracy.

Question 37

In the context of Gypsum-DL, how does considering multiple ionization states improve the preparation of small-molecule libraries for virtual screening?

Answer 37

It accounts for the fact that a molecule’s charge varies with pH, which can alter binding interactions and affect docking accuracy.

Question 38

Why is it important to address unspecified stereochemistry (including chiral centers and cis/trans isomerism) when preparing 3D small-molecule models for virtual screening?

Answer 38

It ensures that all plausible stereoisomers are generated, since different configurations can dramatically influence binding interactions.

Question 39

Why is it important to consider tautomeric forms during the preparation of small-molecule models for virtual screening?

Answer 39

It accounts for the fact that different tautomeric forms can have different hydrogen-bonding patterns, which may alter binding interactions.

Question 40

Why is final geometry optimization a crucial step in preparing small-molecule libraries for virtual screening?

Answer 40

It refines the 3D structures to achieve realistic, low-energy conformations that more accurately mimic the molecules’ behavior in a biological environment.

Question 41

Why are molecular force fields important in the conversion of 2D representations to 3D models for virtual screening?

Answer 41

They are used to optimize molecular geometries and energy states, ensuring that the resulting 3D models represent realistic conformations Accurate energy minimization through force fields is critical for obtaining structures that will perform well in docking simulations.

Question 42

Why is it important to remove salts from molecular databases when preparing small-molecule models for computational studies?

Answer 42

Salts are often included in molecular databases but do not necessarily contribute to biological activity, so they should be removed to improve database accuracy.

Question 43

Why is chirality important when modeling small molecules for computational studies?

Answer 43

Chirality affects molecular recognition, and different enantiomers of a molecule can have different biological activities. Many biological molecules, including proteins and enzymes, are chiral, meaning they interact differently with different enantiomers. For example, one enantiomer of a drug may be active while the other is inactive or even harmful.

Question 44

Why is cis-trans isomerism important when modeling small molecules for computational studies?

Answer 44

Cis-trans isomerism affects molecular shape and can influence biological activity, as different isomers may bind differently to target proteins.

Question 45

Which of the following best describes the difference between tautomers, chiral centers, and cis-trans isomers?

Answer 45

Tautomers are structural isomers that interconvert through the movement of a proton and a double bond, chiral centers involve four different substituents around a single carbon atom, and cis-trans isomers arise from restricted rotation around a double bond or ring system. environment dependent

Question 46

Which of the following best describes the difference between bonded and non-bonded interactions in molecular force fields?

Answer 46

Bonded interactions include bond stretching, angle bending, and torsional forces, while non-bonded interactions include van der Waals and electrostatic forces.