Zheng exam - SAR strats

What are the major phases of drug discovery and development?

Target identification; hit-to-lead; lead optimization; preclinical development; clinical trials; NDA; post-market studies.

Which phase follows hit-to-lead?

Lead optimization.

What is medicinal chemistry's central role in early drug discovery?

Design and optimize compounds to improve potency, selectivity, and druglike properties.

Why is drug discovery considered interdisciplinary?

It combines science and business and is risky, expensive, time-consuming, and time-sensitive.

What does PK-ADMET stand for in drug development context?

Pharmacokinetics and absorption, distribution, metabolism, excretion, and toxicity.

What are common sources for identifying potential drug targets?

Genetics/genomics, proteomics, bioinformatics, and literature mining; AI may also help.

What does target validation assess?

Whether a target is causally relevant, druggable, and safe to modulate.

What types of evidence can help validate a drug target?

Animal models, cellular models, clinical evidence, and genetic manipulation.

How can gene knockout or knockdown help validate a target?

They test how reducing or eliminating the gene affects the biological system or disease phenotype.

How can gene induction help validate a target?

It tests how increasing target expression affects the biological system or disease phenotype.

What does the lecture identify as the final validation of a target?

FDA approval.

What is a drug-discovery hit?

A compound with reproducible, relevant biological activity and evidence supporting further optimization.

Why must hit activity be reproducible?

To distinguish genuine activity from experimental noise or chance results.

Why validate a hit in orthogonal assays?

To confirm activity using a different assay principle and reduce assay-specific artifacts.

Why must a hit have confirmed structure and high purity?

To ensure the measured activity can be attributed to the intended compound rather than impurities or misidentification.

Why should a hit show specificity for its target?

To support that the observed activity is related to the target under study.

Why are clear SAR among hit analogues useful?

They show that structural changes predictably affect activity and give a path for optimization.

Why is novelty considered when evaluating a hit?

A potentially novel compound may offer new intellectual-property opportunities.

What does chemical tractability mean for a hit?

Its structure can be modified and synthesized practically during optimization.

What is the main goal of hit-to-lead work?

Intensive SAR to improve potency and selectivity while incorporating druglike properties.

What characteristics help a hit qualify as a lead?

In vivo activity, no obvious toxicity liabilities, no problematic reactive functions, and patent opportunities.

What is hERG toxicity?

A toxicity liability involving the human ether-a-go-go-related potassium channel.

Why are chemically reactive functions often undesirable in leads?

They can create safety or toxicity liabilities, although exceptions exist.

What is the primary focus of lead optimization in this lecture?

Improving PK-ADMET properties toward a clinical drug candidate.

What are advantages of natural products as hit/lead sources?

They are structurally diverse and remain important sources of leads and drugs.

What are two limitations of natural-product discovery?

Natural material may be limited or difficult to scale up, and novel structures can be hard to find.

What are synthetic compound libraries used for?

Systematic screening to identify active starting compounds.

What does the 'me too, me better' strategy use?

Known active molecules as starting points for similar or improved compounds.

What is drug repurposing?

Finding a new therapeutic use for an existing or old drug.

How did thalidomide's use change?

A failed sedative became an anticancer immunomodulatory drug and a ligand used in molecular-glue and PROTAC strategies.

What new role does thalidomide play in molecular glues and PROTACs?

It can act as a ligand for CRBN to recruit proteins for degradation-related strategies.

What is deflazacort an example of?

Repurposing an anti-inflammatory drug for Duchenne muscular dystrophy treatment.

What is a DNA-encoded library (DEL)?

A collection of small molecules tagged with unique DNA-sequence barcodes.

What is the purpose of DNA barcodes in DEL?

They identify which compound is associated with a binding or screening result.

How large can DNA-encoded compound libraries be?

Billions to trillions of compounds.

What is split-and-pool combinatorial chemistry?

A library-building strategy that repeatedly splits building blocks into groups, reacts them, and pools them to generate many combinations.

What is serendipitous hit discovery?

Finding active compounds by chance, combined with the preparedness to recognize their significance.

What is systematic hit discovery?

Planned approaches such as high-throughput screening, low-throughput screening, virtual screening, and bioassays.

What does HTS stand for?

High-throughput screening.

What is virtual screening?

Computationally prioritizing compounds for potential activity before or alongside experimental testing.

What is phenotype screening?

Screening compounds for effects on a biological phenotype rather than starting solely from a defined molecular target.

How can a natural ligand or substrate provide a starting point?

Its structure and interactions can inspire compounds that modulate the same target.

What is the relationship between serotonin and ondansetron in the lecture example?

Serotonin is the natural ligand; ondansetron is a 5-HT3 receptor antagonist.

What drug class is fluoxetine?

A selective serotonin reuptake inhibitor (SSRI).

What is the 'use other's leads/drugs' strategy?

Building on leads or drugs reported by other researchers or organizations.

What target interaction is discussed for MRTX0902?

SOS1:KRAS protein–protein interaction; the slide reports SOS1 binding Ki of 1.9 nM and MKN1 cellular IC50 of 29 nM.

What does PPI mean in the SOS1:KRAS example?

Protein–protein interaction.

What is the SOSA approach?

Selective Optimization of Side Activities.

What is the central idea of SOSA?

Optimize a useful side activity of a known molecule while reducing or eliminating its original activity.

What did the sulfonamide/tolbutamide example illustrate?

Antibacterial sulfonamides can cause hypoglycemia; optimization separated desired antidiabetic activity from antibacterial activity.

How does tolbutamide lower blood glucose according to the slide?

It inhibits ATP-sensitive potassium channels on pancreatic beta-cell membranes, triggering insulin release.

What is target repurposing?

Using an existing molecule at a different therapeutic target or for a different indication.

How was sildenafil's therapeutic use discovered?

It was designed as a vasodilator for angina and hypertension, but clinical trials revealed efficacy for erectile dysfunction.

Which other PDE5 inhibitors are named alongside sildenafil?

Tadalafil and vardenafil.

What is fragment-based hit discovery?

Finding small, fragment-sized molecules that bind a target and then optimizing or growing them.

What molecular-weight range defines fragments in this lecture?

Approximately 150–300 Da.

How potent are fragment hits compared with typical HTS hits, as described here?

Fragments are often less potent: roughly mM–30 μM versus 30 μM–nM for HTS hits.

What is the relative hit-rate advantage of fragment screening in the lecture?

The hit rate can be 10–1000 times higher.

Why does fragment-based discovery require sensitive biophysical techniques?

Fragments often bind weakly, so sensitive methods are needed to detect their interactions.

Which methods are listed for fragment screening or characterization?

SPR, MST, NMR, X-ray crystallography, and MS, especially for covalent fragments.

What does SPR stand for?

Surface plasmon resonance.

What does MST stand for?

Microscale thermophoresis.

Why is MS especially useful for covalent fragment screening?

It can detect mass changes associated with covalent fragment attachment.

What is affinity selection-mass spectrometry (ASMS) used for?

Identifying compounds that bind a target by affinity selection followed by mass spectrometric analysis.

What questions should be addressed before starting SAR synthesis?

Whether suitable in vitro and in vivo assays can assess compound activity and toxicity.

Why might in vivo pharmacokinetics be worth measuring early?

It can reveal exposure-related issues that may affect whether activity translates in vivo.

What does DMTE stand for in the optimization cycle?

Design–Make–Test–Evaluate.

What are the major goals of hit-to-lead and lead optimization?

High potency, selectivity, and efficacy; overcoming ADME barriers; and producing intellectual property.

Why is SAR case-by-case?

The relevant structural changes depend on which property or properties need improvement.

Why is rapid bioassay feedback important during SAR?

It lets chemists quickly assess design changes and guide the next round of synthesis.

How can co-crystal structures accelerate SAR?

They reveal ligand-binding interactions and can guide structure-based design and optimization.

Why include in vitro and in vivo pharmaceutical-property studies during optimization?

To identify developability, exposure, and safety issues beyond target activity.

Can multiple optimization approaches be applied to the same target?

Yes; the lecture illustrates several complementary approaches for the same target.

What does SBDD stand for?

Structure-based drug design.

What does FBDD stand for?

Fragment-based drug discovery.

What target family is used as an example of multiple approaches in the lecture?

XIAP/cIAP ligands.

What methods were used in the XIAP/cIAP example?

Structure-based drug design, fluorescence polarization assays, NMR analysis, peptide libraries, capped tripeptide libraries, and fragment screening.

What is the purpose of a fluorescence polarization (FP) assay in ligand discovery?

To assess binding interactions through changes in fluorescence polarization.

How was fragment-based discovery used in the XIAP/cIAP example?

Fragments were screened by NMR and their binding modes were examined using co-crystal structures.

What is the role of co-crystal structures in lead optimization?

They guide changes that improve binding potency and selectivity.

What does SAR mean?

Structure–activity relationship: how structural changes affect biological activity.

What properties can SAR changes influence?

Potency, selectivity, and efficacy.

What does SPR mean in this lecture's SAR terminology?

Structure–property relationship.

What physicochemical properties are examples of SPR outcomes?

Solubility, lipophilicity, ionization, and permeability.

What is point SAR?

How localized changes, such as adding or replacing a substituent at one position, affect activity.

What is scaffold SAR?

How changes to the core molecular framework affect activity.

What is chirality SAR?

How stereochemistry, including enantiomers or diastereomers, affects activity.

What is ligand efficiency (LE)?

Binding affinity normalized by the number of non-hydrogen (heavy) atoms.

What is the lecture's approximate equation for ligand efficiency?

LE ≈ 1.37 × pKd / heavy-atom count, in kcal·mol⁻¹ per heavy atom.

What does a high ligand efficiency indicate?

A molecule achieves relatively strong binding affinity for its size.

What is lipophilic ligand efficiency (LLE or LipE)?

Potency considered relative to lipophilicity.

What is the lecture's equation for LLE?

LLE = pIC50 − logP, or pKd − logP.

Why can LLE be useful during optimization?

It helps assess whether potency gains justify increased lipophilicity.

What is the 'me too' approach in SAR?

Analogue design based on known active compounds.

What is the usual assumption behind true analogue design?

Similar structures often produce similar pharmacology.

What are true analogues?

Structurally similar compounds with similar pharmacology.

What are structural analogues in this lecture's classification?

Structurally similar compounds that can have different pharmacology.

What are functional analogues?

Structurally different compounds that produce similar pharmacology.

Which drug class is illustrated by losartan, valsartan, candesartan, irbesartan, and telmisartan?

Angiotensin II AT1 receptor antagonists.

What do the AT1 antagonist examples illustrate?

True analogues developed around a related pharmacological activity.