MCHM3001 · From Molecules to Therapeutics
The Druggable Proteome & Modulating Gene Expression
Lectures 5–6 of MCHM3001 expand what counts as a target — beyond the classic enzyme/receptor pocket into protein-protein interactions, targeted degradation and pharmacological chaperones — and then treat the nucleic-acid drugs (antisense oligonucleotides, siRNA/miRNA, mRNA) that modulate gene expression directly. The examinable threads are the druggable-versus-target distinction, beyond-rule-of-5 space, and the RISC and ubiquitin-proteasome mechanisms. It recurs in Test 1 and the final.
What this chapter covers
- 01Druggable ≠ drug target: druggable = binds a drug-like small molecule; a target must also be disease-linked and disease-modifying (~85% of the proteome currently 'undruggable')
- 02Protein families of drug targets (GPCRs, kinases, Zn metallopeptidases e.g. MMP-3, serine proteases, nuclear receptors, phosphodiesterases)
- 03Beyond-rule-of-5 (bRo5) space and PPI inhibitors — venetoclax (MW 868, cLogP 10.4) disrupting BCL-2:BIM to restore apoptosis
- 04Occupancy-driven versus event-driven pharmacology; the ubiquitin-proteasome system (E1→E2→E3, Lys48 chains, 26S proteasome)
- 05PROTACs: heterobifunctional degraders (POI ligand-linker-E3 ligand), catalytic, enabling 'undruggable' targets
- 06Pharmacological chaperones — tafamidis stabilising the transthyretin tetramer
- 07Antisense oligonucleotides (ASOs): PS, PMO, 2'-OMe and GalNAc chemistries; block translation, recruit RNase H, or alter splicing
- 08RNAi (siRNA/miRNA) via the RISC/Argonaute pathway; mRNA therapeutics (pseudouridine, LNP delivery); CRISPR/Cas9 (NHEJ vs HDR)
Why a beyond-rule-of-5 molecule can still be an oral drug
- +1Recall the four Lipinski limits: MW < 500, HBD < 5, HBA < 10, cLogP < 5.
- +1Test each: MW 868 > 500 (violation); HBA 14 > 10 (violation); cLogP 10.4 > 5 (violation); HBD 3 < 5 (OK). That is 3 violations — venetoclax sits well beyond rule-of-5 (bRo5) space, where the 'no more than one violation' guideline is broken.
- +1Explain the target class: venetoclax is a protein-protein-interaction (PPI) inhibitor. It binds BCL-2 and disrupts the BCL-2:BIM interaction, freeing pro-apoptotic signalling so cancer cells (CLL) can undergo apoptosis. PPI surfaces are large and flat, which forces larger, more lipophilic molecules than a classic enzyme pocket.
- +1Explain how it overcomes its poor properties: extremely high affinity (Ki < 0.01 nM) means little drug is needed at the target, and formulation tricks (a lipidic formulation and a positive food effect) rescue oral exposure despite the poor solubility that bRo5 space implies.
Key terms
- Druggable vs drug target
- Druggable means a protein binds a drug-like small molecule with useful affinity; a drug target must additionally be disease-linked and disease-modifying. About 85% of the proteome is currently considered undruggable.
- Beyond rule of 5 (bRo5)
- Chemical space outside Lipinski's limits (MW, HBD, HBA, cLogP), occupied by ~6% of oral drugs and a rising share of new oral approvals — typically PPI inhibitors, macrocycles and oligonucleotides.
- PPI inhibitor
- A molecule that blocks a protein-protein interaction rather than an enzyme active site; e.g. venetoclax disrupting BCL-2:BIM to restore apoptosis. PPI surfaces are large and flat, favouring larger lipophilic ligands.
- PROTAC
- A heterobifunctional degrader with a target-protein ligand, a linker and an E3-ligase ligand; it recruits an E3 ligase to poly-ubiquitinate the target for proteasomal destruction. It is catalytic (event-driven) and can reach 'undruggable' proteins.
- Antisense oligonucleotide (ASO)
- A short (13–25 nt) modified single-stranded DNA that blocks translation, recruits RNase H to degrade its target mRNA, or alters splicing (exon skipping). Chemistries (PS, PMO, 2'-OMe, GalNAc) fix its poor stability and delivery.
- RISC / RNAi
- The RNA-induced silencing complex (with Argonaute) that siRNA and miRNA use: the passenger strand is discarded and the guide strand directs cleavage or repression of complementary mRNA.
The Druggable Proteome & Modulating Gene Expression FAQ
Why is most of the proteome called 'undruggable'?
Because a classic drug needs a well-defined pocket to bind with useful affinity, and most proteins — especially those acting only through flat protein-protein interfaces — do not offer one. Up to ~85% of the proteome falls into this category. New modalities (PPI inhibitors, PROTAC degraders, pharmacological chaperones and oligonucleotide therapies) are the strategies MCHM3001 teaches for expanding the druggable proteome.
How does a PROTAC differ from a conventional inhibitor?
A conventional inhibitor is occupancy-driven: it must stay bound to block the target's function, so you need sustained exposure. A PROTAC is event-driven: it is a heterobifunctional molecule that brings the target and an E3 ubiquitin ligase together, the target is poly-ubiquitinated (Lys48 chains) and destroyed by the 26S proteasome, and the PROTAC is released to act catalytically. That lets it degrade targets with no classic druggable pocket.
What is the difference between an ASO and siRNA?
Both silence gene expression but by different routes. An antisense oligonucleotide is a single strand of modified DNA that can block translation, trigger RNase H cleavage of the mRNA, or redirect splicing. siRNA is double-stranded and works through the RISC/Argonaute pathway, where the guide strand directs cleavage of complementary mRNA. siRNA is usually highly specific to one target, whereas miRNA hits many.
Can AI help me learn the druggable-proteome and gene-modulation material?
Yes. Sia can drill the druggable-versus-target distinction, explain why beyond-rule-of-5 molecules like venetoclax still work, walk through the ubiquitin-proteasome and RISC pathways, or contrast ASO chemistries (PS, PMO, GalNAc). It explains the mechanism and checks your reasoning; it will not do graded assessment for you, and University of Sydney academic-integrity rules apply.
Exam move
Split this chapter into two halves and keep both warm. For the druggable-proteome half, be able to justify 'druggable but not a target' and name the new modalities (PPI inhibitors, PROTACs, pharmacological chaperones, oligonucleotides) with one worked example each — venetoclax for bRo5 PPIs is the safest. For the gene-modulation half, draw the RISC pathway and the ubiquitin-proteasome cascade, and tabulate the nucleic-acid drugs (ASO, siRNA, miRNA, mRNA) by what they target and how they are chemically stabilised. Practise counting Lipinski violations quickly, because that skill returns in the screening and hit-to-lead chapters. When a mechanism (Lys48 chains, RNase H recruitment) is fuzzy, ask Sia to redraw it step by step.
Working through The Druggable Proteome & Modulating Gene Expression in MCHM3001? Sia is AskSia’s AI Chemistry tutor — ask any MCHM3001 The Druggable Proteome & Modulating Gene Expression question and get a clear, step-by-step explanation grounded in how MCHM3001 is taught and assessed. Read this chapter free, then take your hardest questions to Sia.
