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MCHM3001 · From Molecules to Therapeutics

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Chapter 9 of 13 · MCHM3001

Lead Optimisation

Lectures 14–15 of MCHM3001 cover how a lead is refined into a candidate: the design-make-test-analyse cycle, structural simplification of complex natural products, strategies to enhance binding, and bioisosteric replacement to tune potency, lipophilicity and metabolism. The examinable skills are reasoning about structure-activity relationships and efficiency metrics such as LipE. It builds on hit-to-lead and appears in Test 2 and the final.

In this chapter

What this chapter covers

01The DMTA cycle: Design → Make → Test → Analyse, iterating across modelling, synthesis and in-vitro DMPK
02Properties tracked: structural (H-bonding, lipophilicity, MW, pKa, PSA), physicochemical, biochemical and PK/tox
03Structural simplification of natural products (halichondrin B → eribulin; myriocin → fingolimod), retaining the pharmacophore
04Enhancing binding: varying alkyl/aryl substituents, extensions into hydrophobic pockets, chain and ring expansion/contraction
05Isosteres and bioisosteres: classical (F/H, OH/NH₂, -CH₂-/-O-) and non-classical (carboxylic-acid isosteres: tetrazole, acylsulfonamide)
06Fluorine as an H-isostere: increasing permeability and oral exposure, blocking metabolic soft spots
07Carboxylic-acid isostere SAR (angiotensin-II biphenyl series IC50 275 → 3 nM) and bicyclo[1.1.1]pentane as a phenyl bioisostere
08Scaffold hopping (change the core, keep activity, gain IP) and improving metabolic stability by N-incorporation

Worked example · free

Potency versus lipophilic efficiency in an analogue pair

Q [4 marks]. Two analogues from a DMTA cycle are compared. Analogue A: IC50 = 100 nM, logP = 4.0. Analogue B: IC50 = 10 nM, logP = 5.5. Using LipE = pIC50 − logP (pIC50 = −log₁₀ of IC50 in molar), decide which analogue is the better optimisation and explain why raw potency can mislead. (4 marks)

+1Convert IC50 to pIC50. Analogue A: 100 nM = 1 × 10⁻⁷ M → pIC50 = 7.0. Analogue B: 10 nM = 1 × 10⁻⁸ M → pIC50 = 8.0. So B is ten-fold more potent.
+1Compute LipE for A: LipE = pIC50 − logP = 7.0 − 4.0 = 3.0.
+1Compute LipE for B: LipE = 8.0 − 5.5 = 2.5. So although B is more potent, its LipE is LOWER than A's.
+1Interpret: B's extra potency was 'bought' by adding lipophilicity (logP rose 4.0 → 5.5), not by better, more efficient binding. Higher logP tends to worsen solubility, metabolic stability and off-target/hERG risk, so by lipophilic efficiency A (LipE 3.0) is the better-optimised, more developable analogue.

pIC50: A = 7.0, B = 8.0; LipE: A = 3.0, B = 2.5. Analogue B is ten-fold more potent but less lipophilically efficient — its potency came from added greasiness. Analogue A, with the higher LipE, is the better optimisation because its affinity is not just a product of high logP.

Sia tip — Always convert IC50 to pIC50 first (−log₁₀ of the molar value: 100 nM → 7, 10 nM → 8), then subtract logP. The teaching point is that chasing raw IC50 can just be adding lipophilicity; LipE exposes that. Ask Sia to build you an analogue table and have you rank by LipE, not IC50.

Glossary

Key terms

DMTA cycle: The iterative Design-Make-Test-Analyse loop of lead optimisation, cycling between molecular modelling/SAR, synthesis and in-vitro DMPK and biology.
Structural simplification: Removing non-essential parts of a complex (often natural-product) lead while retaining the pharmacophore, to make it synthesisable and drug-like — e.g. halichondrin B → eribulin, myriocin → fingolimod.
Bioisostere: A group substituted for another to keep biological activity while improving a property; classical (F for H, OH for NH₂) or non-classical (carboxylic-acid isosteres such as tetrazole or acylsulfonamide).
Fluorine substitution: Using fluorine as a hydrogen isostere to raise permeability and oral exposure, lower the basicity of a neighbouring group, or block a metabolically labile site (the strong, inert C-F bond resists oxidation).
Scaffold hopping: Replacing the core of a lead while preserving the pharmacophore and activity, to gain fresh intellectual property, remove reactive metabolites, or improve metabolic stability.
Lipophilic efficiency (LipE): LipE = pIC50 − logP; it rewards potency that comes from specific interactions rather than added lipophilicity, so a higher LipE signals a more developable analogue.

FAQ

Lead Optimisation FAQ

Why can chasing raw potency (IC50) mislead during optimisation?

Because potency can be increased simply by making a molecule greasier — more lipophilic groups often bind hydrophobic pockets better — but high logP brings poor solubility, faster metabolism, and greater off-target and hERG risk. Lipophilic efficiency (LipE = pIC50 − logP) strips out the contribution of lipophilicity, so it reveals whether an analogue is genuinely binding better or just heavier and greasier. The higher-LipE analogue is usually the better lead even if it is not the most potent.

What is structural simplification and why do it?

It is the deliberate removal of parts of a complex lead — usually a natural product — that are not needed for binding, while keeping the pharmacophore intact. It makes the molecule far easier and cheaper to synthesise and often improves drug-like properties. Classic MCHM3001 examples are halichondrin B simplified to eribulin and myriocin simplified to fingolimod.

How is fluorine used in lead optimisation?

Fluorine is a small, versatile hydrogen isostere. Swapping an H for an F can increase membrane permeability and oral exposure, lower the basicity of a nearby ionisable group, or, most commonly, block a metabolic soft spot — the strong and biologically inert C-F bond resists the oxidation a C-H would undergo, improving metabolic stability without greatly changing shape.

Can AI help me with lead optimisation in MCHM3001?

Yes. Sia can compute and compare LipE across an analogue series, explain a bioisosteric replacement, walk through the DMTA cycle, or reason about an SAR trend such as the carboxylic-acid isostere series. It explains the medicinal-chemistry logic and checks your reasoning; it does not do graded assessment for you, and University of Sydney academic-integrity rules apply.

Study strategy

Exam move

Treat lead optimisation as reasoning practice rather than memorisation. Rehearse the LipE calculation until converting IC50 to pIC50 and subtracting logP is automatic, and always ask whether a potency gain came from better binding or just more lipophilicity. Keep a short catalogue of bioisosteric moves (F for H, carboxylic-acid isosteres, ring simplification, scaffold hops) each tied to the property it fixes, and be able to read an SAR table and pick the best compound on efficiency, not raw IC50. Anchor the DMTA cycle as the loop that ties modelling, synthesis and testing together. When an SAR trend confuses you, ask Sia to rank an analogue series and justify the winner.

Working through Lead Optimisation in MCHM3001? Sia is AskSia’s AI Chemistry tutor — ask any MCHM3001 Lead Optimisation 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.

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