nucleic lec 12

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Questions and Answers

What is a defining characteristic of a drug?

It produces side effects that are always negligible.

It must bind to a biological target. (correct)

It originates only from natural sources.

It is always a synthetic compound.

What was one of the primary benefits of acetylating salicylic acid to form aspirin?

It increased the potency of the drug by tenfold.

It created a new pathway in drug synthesis techniques.

It reduced gastrointestinal distress compared to salicylic acid. (correct)

It eliminated all side effects associated with the drug.

Why is target identification crucial in drug discovery?

It helps to focus the drug’s action on specific biological molecules. (correct)

It ensures the drug has minimal production costs.

It eliminates the need for clinical trials.

It guarantees a drug’s effectiveness in all patients.

What role do high throughput screening methods play in drug discovery?

They allow for rapid testing of multiple compounds against targets. Signup and view all the answers

What is a key challenge faced during clinical trials?

Recruiting a sufficiently diverse and representative patient population. Signup and view all the answers

What percentage of compounds in clinical trials typically fail to receive approval?

80 - 90% Signup and view all the answers

What is an important criterion in selecting a target for drug discovery?

Its structure Signup and view all the answers

Which phase follows the identification of drug 'hits'?

Lead optimization Signup and view all the answers

What is the typical volume for a high throughput screening (HTS) test?

< 1 µl Signup and view all the answers

What might cause a 'hit' to be deemed unsuitable during the transition to 'leads'?

Non-specific interactions Signup and view all the answers

Which aspect does lead optimization primarily focus on improving?

Affinity and selectivity Signup and view all the answers

What is the average cost and duration to develop and approve a new drug?

$2 billion and 15 years Signup and view all the answers

What is the primary goal of high throughput screening (HTS)?

Finding compounds that bind to a target Signup and view all the answers

What is one of the initial steps in the drug development process after discovering a drug candidate?

Conduct in vitro and animal trials for safety Signup and view all the answers

What does the drug development phase known as 'lead optimization' primarily focus on?

Enhancing drug affinity and specificity Signup and view all the answers

In drug development, what is the purpose of pre-clinical trials?

To evaluate safety and efficacy in laboratory settings Signup and view all the answers

What do the phases of clinical trials primarily aim to achieve after pre-clinical testing?

Prove safety and efficacy in human subjects Signup and view all the answers

Which factor must be established before a drug can be marketed to patients?

It must have been approved by a government body Signup and view all the answers

Which of the following is a crucial aspect of risk assessment in drug development?

Careful evaluation of potential adverse effects Signup and view all the answers

What is a common challenge faced during clinical trials?

Obtaining an adequate number of suitable volunteers Signup and view all the answers

Which aspect is NOT typically tested during the lead discovery phase?

Market viability Signup and view all the answers

Which property is NOT essential for orally available drugs?

High molecular weight for increased stability Signup and view all the answers

What role does computational anticipation of properties play in drug development?

It minimizes resource requirements for drug projects Signup and view all the answers

What is the hit rate achieved by the virtual fragment screening innovation mentioned?

33% Signup and view all the answers

Which factor does NOT contribute to the successful absorption of a drug in the body?

Tight binding to target Signup and view all the answers

Why is it important for drugs to minimize cross reactions?

To maintain efficacy at low concentrations Signup and view all the answers

What recent advancement has been utilized for docking in drug discovery?

AlphaFold 2 models Signup and view all the answers

Which characteristic is important for a drug to pass through cell membranes?

High lipophilicity Signup and view all the answers

What is the primary benefit of using computational methods in drug screening?

They enable virtual screening of drug-like molecules. Signup and view all the answers

Which statement best describes the role of AF3 in drug discovery?

It can enhance virtual screening and affinity optimization. Signup and view all the answers

What unique advantage does computational pre-screening provide in drug development?

It identifies unexploited interactions for binding energy. Signup and view all the answers

Which of the following is NOT a feature of AF3 and related tools in drug discovery?

They allow for real-time adjustments during clinical trials. Signup and view all the answers

Which challenge can be mitigated through the use of AF3 in drug discovery?

The cost associated with physical drug trials. Signup and view all the answers

What does AF3's capability to predict complex structures aim to achieve in drug optimization?

Improving the likelihood of effective drug-target interactions. Signup and view all the answers

How does having the structure of a target influence drug discovery?

It provides a framework for pre-screening compounds. Signup and view all the answers

What is the primary mechanism by which Aspirin exerts its effects?

Inhibiting the synthesis of prostaglandins Signup and view all the answers

What specific enzyme does Aspirin irreversibly inhibit?

Cyclooxygenase 2 (COX-2) Signup and view all the answers

What does the acetylation of Ser530 by Aspirin result in?

Formation of a covalent bond Signup and view all the answers

What is a possible consequence of random modifications in drug design as stated in the content?

Creation of highly addictive drugs Signup and view all the answers

What distinguishes salicylic acid's action from that of Aspirin?

It binds to the same pocket as Aspirin but does not acetylate Signup and view all the answers

What is the main effect of COX-2 in the body?

It synthesizes prostaglandins. Signup and view all the answers

How does Aspirin acetylate Ser530 in COX-2?

By acetylating the side chain of Ser530. Signup and view all the answers

What does the 'A' in ADME Tox stand for?

Absorption Signup and view all the answers

Which of the following best describes the term 'Metabolism' in the context of ADME Tox?

The breakdown of the compound by the liver Signup and view all the answers

What is the significance of considering ADME-Tox issues early in drug development?

To avoid designing inherent problems into the compound Signup and view all the answers

What does the 'Toxicity' aspect in ADME Tox refer to?

The adverse side effects caused by the drug Signup and view all the answers

Which of the following is not a component of ADME Tox?

Detection Signup and view all the answers

Which method is known for revealing the binding site AND mode in fragment screening?

X-ray Crystallography Signup and view all the answers

What is a notable advantage of using NMR for measuring ligand binding?

It can detect very weakly binding ligands. Signup and view all the answers

What is a key reason for using crystallography in fragment screening?

It shows how multiple fragments can interact with each other. Signup and view all the answers

What can influence the design of a linker in linking two closely binding fragments?

Knowledge of fragment co-structures. Signup and view all the answers

Which binding energy characteristic is important when linking two millimolar binders?

Binding energies are additive. Signup and view all the answers

Which method can detect binding but does not provide information about binding mode or site?

Surface Plasmon Resonance Signup and view all the answers

What advantage does fragment screening with crystallography provide over other methods?

It reveals how ligands bind and coordinate their interactions. Signup and view all the answers

What is the concentration at which very weakly binding ligands can be detected using NMR?

mM Signup and view all the answers

Match each method with a specific capability of detecting protein-ligand interactions:

Native Mass Spectrometry = ✔️ Detects Binding NMR = ✔️ Reveals Binding Site X-ray Crystallography = ✔️ Shows Binding Mode Surface Plasmon Resonance = ✔️ Reveals Affinity Signup and view all the answers

Match the following methods to the interactions they can detect:

Native Mass Spectrometry = Binding Only NMR = Binding and Site X-ray Crystallography = Binding, Site, and Mode Surface Plasmon Resonance = Binding Only Signup and view all the answers

Study Notes

Structural Biology in Drug Discovery

Drug discovery employs structural biology to identify and predict drug function.
Drugs are chemical entities causing desired therapeutic effects.
These entities can be small molecules (natural, synthetic, or semi-synthetic) or proteins (from natural sources or recombinant).
Drugs work by specifically binding and affecting a protein or other biological target.

Drug Targets

Common targets are proteins, but DNA and RNA may also be targets.
Effective drugs target only one or a few biological molecules.
The target is selected so that effective chemical interventions efficiently produce the desired effect.

Historical Example - Aspirin

Hippocrates recognized willow bark's pain-relieving properties.
Salicylic acid, extracted from willow bark, was later identified as the active ingredient.
Researchers modified salicylic acid to form acetyl salicylic acid (aspirin).
Aspirin has fewer gastrointestinal side effects than salicylic acid.
Aspirin inhibits the synthesis of prostaglandins through the inhibition of cycloxygenase 2 (COX-2).

How Aspirin Works

Aspirin inhibits COX-2 by acetylating Ser530.
COX-2 is an inducible oxygenase that synthesizes prostaglandins, mediators of inflammation and chronic pain.

Aspirin Limitations

Acetylation can be applied to other natural products, like morphine.
Early drug development had riskier practices compared to modern standards

Modern Drug Development

Today, new drugs need extensive in vitro and animal testing before human trials.
Modern drug development processes ensure that a drug candidate demonstrates safety and efficacy.
Many compounds fail to meet the stringent criteria set for regulatory approval.

Conceptual Drug Invention

Drug invention begins with understanding the "disease" state.
Mechanistic understanding leads to identifying a possible route for therapeutic intervention.
Systematic search for a chemical that hits the target.

Drug Candidate Development

Lead discovery involves identifying preliminary molecules with desired activity.
Lead optimization involves affinity, selectivity, toxicity, property refinement.
A drug candidate goes through pre-clinical testing and three phases of clinical trials.
The average drug takes ~15 years and costs ~US$2 billion to develop and approve.

Target Identification

Drug discovery often focuses on finding compounds affecting specific molecular targets (usually proteins).
The selected target enables effective chemical intervention for the desired biological outcome.
Common targets include the first committed step of an enzymatic pathway or the receptor of a signal transduction pathway.
Protein structure is crucial as it indicates how "druggable" a target is.

High-Throughput Screening (HTS)

HTS is traditionally the first step in identifying a new drug.
Screening involves a large library (~10⁵-10⁶) of synthesized organic compounds, for potential drug candidates.
A biochemical or cell-based assay identifies if a compound binds to the target.

Transforming Hits to Leads

Hits are compounds exhibiting positive assay results but not necessarily producing the desired pharmacological effect.
Subsequent testing involves evaluating and eliminating compounds not meeting criteria, such as being toxic, too difficult to synthesize or non-specific
“Leads” are compounds confirmed to demonstrate the desirable bio-chemical response and eligible for further investigation.

Lead Optimization

Modifying lead compounds to improve affinity, selectivity, toxicity, and other pharmacokinetic parameters.
This often requires synthesizing many new compounds, with extensive testing on activity, selectivity, and other qualities.
Leads may have 10 µM binding constants, and the development candidates need ~1 nM binding constants.

Properties of Orally Available Drugs

Binding of the drug to the target must be tight with the target (in the low nanomolar range) to ensure effective action at low concentrations.
The drug needs to be readily absorbed, dissolved into membranes, and transported out of cells efficiently.
Large molecules often face challenges in crossing cell membranes; optimal size is important
Favorable chemical properties contribute to greater success during drug development.

Drug Candidate Chemical Properties

Drug candidates should ideally have few or no chiral centers, for easier synthesis in good yields.
The presence of chiral centers in the structure impacts the production of a desired quantity and prevents the development of undesired properties.
Minimizing free rotatable bonds is critical to reducing conformational entropy in a drug molecule.

ADME-Tox

Assessing the Absorption, Distribution, Metabolism, Excretion, and Toxicity of drug candidates in the body.
These factors ensure the efficacy and safety of a drug by evaluating its interaction and metabolism within the body.
Early identification of associated problems are crucial.

Structure-Guided Drug Discovery (SGDD)

Using structural biology to measure and predict drug function and binding.
Drug development can leverage protein structures to predict drug binding and guide medicinal chemistry.

Experimental Structures for Rationalization

Experimental structures (e.g., X-ray crystallography) help rationalize how new compounds bind.

Fragment Screening

Fragment screening is a "divide and conquer" approach for drug discovery by focusing on small molecules.
Methods like native mass spectrometry or surface plasmon resonance can identify weak binders.

NMR for Ligand Binding

Monitoring ligand binding using NMR identifies changes in chemical shifts.

Screening with Crystallography

Screening drug-like fragments using crystallography assists in understanding how the ligand binds, identifying interactions, and evaluating potential modifications.

Linking Fragments

Linking pre-identified fragments that bind in close proximity on the targeted protein enables designing an appropriate linker.
Drug-like molecules, with their size constraints, are prioritized for production.

Computational Chemistry

Computational methods can estimate binding energies, using force fields and molecular dynamics simulations.

MD in Drug Discovery

Molecular dynamics (MD) simulations can evaluate molecular interaction details and binding.

Simplified Scoring Functions

Simplified scoring functions provide quick evaluations for large numbers of molecules by assuming the protein is static.

Approximating Binding Energy

Estimating energy by integrating van der Waals, electrostatic, and hydrogen bond interactions.

Docking

Docking computationally analyzes where ligands bind to target proteins with available structural data.

Virtual Screening

Virtual screening uses iterative docking to examine a large library of candidate molecules.
Ranking compounds based on energy levels guides drug discovery efforts.

"On-Demand" Molecules

"On-demand" molecules are available through customized synthesis, expanding chemical libraries for drug testing.

Virtual Fragment Screening

Focused on testing component fragments, limiting experimentation scope to relevant compounds.

Virtual Screening Against Alphafold Models

Alphafold models have been used in virtual screening to identify new drug compounds.

Alphafold 3 and Beyond

Alphafold 3 and its counterparts hold significant promise in drug target evaluation.

Summary

Computational approaches are powerful tools in circumventing expensive high-throughput screening (HTS).
Understanding a target's structure allows for 'pre-screening' compounds.
Computational tools can predict and incorporate off-target interactions into the workflow for drug screening.

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Description

This quiz explores the role of structural biology in drug discovery, including the identification of drug functions and targets. It highlights how effective drugs interact with specific biological targets, such as proteins, DNA, and RNA. A historical example of aspirin illustrates the process of drug development.