Medicinal Chemistry: Drug Discovery and Design - Comprehensive Study Notes

Drugs are chemicals

• Physical and chemical properties determine whether a chemical compound will function as a drug:

  • Size

  • Shape

  • H-bonding groups

  • Ionic bonding groups

  • Hydrophilicity

  • Acidity and basicity

  • Chirality

  • Metabolism

  • Rate of excretion

  • Toxicity

  • Etc.

Choosing a disease to target

• Considerations for disease targeting:

  • Is the disease common in the population?

  • Is there an unmet clinical need or lack of suitable existing medical products?

  • What drugs are already on the market? Efficacy and toxicity data of these drugs?

• Drug discovery is a costly exercise; pharmaceutical companies seek to market a drug that can recover development and testing costs and earn profit.

• Questions to be addressed:

  • Ultimately, there must be an unmet clinical need which drives the company’s investment.

Target Selection – Types of drug targets

• Drug targets can be:

  • Proteins: Receptors, Enzymes, Carrier proteins, Transporter proteins, Ion channels

  • Nucleic Acids: DNA, RNA

• Example contexts (illustrative): GABA receptor; Doxorubicin interaction with DNA torsion and chromatin dynamics; Doxorubicin-DNA complex.

Target Specificity and Selectivity

• The more selective and specific a drug is for its target, the lower the chance of off-target side effects.

• Specific target selection can be achieved by:

  • Selecting a specific receptor subtype (for receptor agonists or antagonists)

  • Selecting a specific isoform of an enzyme (for enzyme inhibitors)

Example - NSAIDs

• Two cyclo-oxygenase enzymes: COX-1 and COX-2

  • COX-1 regulates physiological functions in the gut and kidney

  • COX-2 is induced in inflammation and repair

• Selective COX-2 inhibitors show a significantly lower incidence of gastrointestinal adverse effects compared to non-selective COX-1/COX-2 inhibitors.

Drug Design and Development

• Generally, new drugs are not readily discovered; lead compounds (prototype with attractive activity) are found.

• Lead compounds often have undesirable characteristics (e.g., high toxicity, other biological activities, poor absorption, insolubility, metabolism issues).

• Lead compounds are modified by synthesis to amplify desired activity and minimise undesired properties.

• Resulting in a clinical drug candidate, a compound worthy of extensive biological, pharmacological, and animal studies.

Sources of lead compounds

• Leads may be of natural or synthetic origin or a mixture (semi-synthetic derivatives of natural products):

  • Natural products: Plant kingdom, Microbes, Marine world, Animal sources, Venoms & toxins, Neurotransmitters and hormones

  • Synthetic products: Chemical synthesis, Library of compounds, Combinatorial synthesis

Finding a Lead Compound

• Approaches include:

  • Starting from the natural ligand or modulator of a target receptor or enzyme as a lead

  • If the biologically active site is known, simple rational design can yield useful compounds

• Example: Captopril designed to inhibit angiotensin‑converting enzyme (ACE) to ease vascular constriction; ACE contains a Zn2+ ion in the active site.

• Natural substance reference: Angiotensin I (as a biological substrate) and a designed inhibitor interacting with the Zn2+ site in ACE.

Finding a Lead Compound – Computer-aided design

• Computer-aided design is powerful when the 3D shape of the receptor is known.

• X-ray crystallography can determine protein structure and binding sites.

• With detailed knowledge of the binding site, molecular modelling software can be used to design new molecules that fit and bind – de novo design.

Finding a Lead Compound – Serendipity

• Serendipitous discovery: example where a drug initially tested for angina surfaced an unexpected beneficial side effect, later marketed as Sildenafil (Viagra).

Drug Design and Development (practical workflow)

• Steps include:

  • Find a lead compound

  • Modify the compound to optimise binding at the active site

  • Identify and improve key binding interactions

  • Identify the pharmacophore (essential features for activity)

  • Modify to optimise access to the target

  • Improve adsorption

  • Reduce metabolism

  • Etc.

Goals

• Primary goals of modification:

  • Increase potency

  • Increase bioavailability

  • Increase therapeutic index (ratio of desirable to undesirable drug effects)

Drug Properties: The Ideal Drug (general expectations)

• Easily administered; preferably oral over intravenous

• Slow-release options for extended dosing (e.g., XR, MR, SR)

• High bioavailability

• Low dose; convenient dosing schedule (e.g., once per day or less)

• Minimal side effects; no allergic reactions

• High therapeutic index

• Low cost

• Easy to synthesise or extract from a natural source

Drug Properties: Key factors for activity

• Structural Properties: $MW, ext{H-bonds}, ext{Lipophilicity}, pK_a, ext{Shape}, ext{Reactivity}$

• Physiochemical Properties: $ext{Solubility}, ext{Permeability}, ext{Chemical Stability}$

• Biochemical Properties: $ext{Transporter affinity}, ext{Binding}, ext{Target affinity}, ext{Metabolism}$

• Physical Environment: $ext{Proteins}, ext{Living Systems}$

• Pharmacokinetics and Toxicity: $ext{Clearance}, ext{Half-life}, ext{Bioavailability}, ext{LD}_{50}$

Drug Design

• Take a lead compound and modify it in a logical fashion:

  • Identify critical binding groups (e.g., ionic bonds, H-bonds, dipole interactions, Van der Waals)

  • Example motif changes in penicillins: a part can be changed while another part is critical for activity

Binding Interactions: Hydrogen Bonds

• Hydrogen-bonding groups include tertiary amines, carbonyls, ethers (H-bond acceptors)

• Lone pairs on O and N can interact with a hydrogen on an electronegative atom

• N can donate one hydrogen bond; O can donate two

• Fluorine can act as a hydrogen-bond acceptor due to high electronegativity

• Most other O/N-containing groups (acids, alcohols, phenols, primary/secondary amines, amides) can be both donors and acceptors

Binding Interactions: Ionic Bonds

• Ionic bonds form between acidic groups (e.g., carboxylate) and basic groups (e.g., ammonium)

• Classic examples: carboxylate

• Representative depiction: O− … NR3+ interactions

Binding Interactions: Dipole Bonds

• Ion‑dipole bonds exist between ionic groups and groups with partial charges

• Dipole–dipole bonds exist between two polar groups with partial charges

Binding Interactions: Van der Waals

• Interactions between aromatic rings and non-polar chains can be weak but cumulative

Lead Modification

• Binding to a receptor is due to one or more interactions; strengthen binding to improve activity

• Modify a lead to: improve existing interactions, create new interactions, replace atoms/groups to enhance binding

Isosteres

• Isosteres are atoms or groups with the same valency (outer-shell electrons)

• Examples: OH has isosteres SH, NH2, CH3; O has isosteres S, NH, CH2

• Isosteres share similar size/shape/electrons but differ in polarity/reactivity

• They allow exploration of binding importance by substituting potential essential groups

Isosteres (detailed properties)

• Changing isosteres may or may not strongly affect the molecule

• Example comparisons illustrate differences in polarity and electron distribution between similar-sized substitutes

• Property table-style contrasts (illustrative): bond lengths, angles, van der Waals radii, logP, electronegativity, van der Waals volume

Isosteres – practical example

• Propanolol: replacing the –O–CH2– unit with other units suggests oxygen may be necessary for activity (e.g., H-bonding or electron-withdrawing effects)

Bioisosteres

• Replace a functional group with another that retains the same biological activity

• Not necessarily the same valency; broader than classical isosteres

• Includes both classical and non-classical isosteres

• Used to replace a problematic group in a lead that is important for binding but causes toxicity or other issues

Drug Modification

• Various modification strategies to optimise activity:

  • Change of substituents

  • Change of substituent size

  • Change of substituent position

  • Addition of substituents

  • Extension/contraction of the structure (ring extension/contraction)

  • Simplification of the structure

  • Rigidification of the structure

Drug Modification: Change of substituents

• Changing easily accessible substituents is a common method

• Vary alkyl substituents; larger groups can enhance Van der Waals interactions with binding sites

• Example: methyl to tertiary-butyl increases hydrophobic contact

• Aromatic groups can be enlarged to maximize interactions; chain extension to fit hydrophobic pockets

• Replacing carbon-skeleton substituents is often synthetically challenging

Example: Salbutamol

• Salbutamol (asthma drug) was developed using neurotransmitters like adrenaline/noradrenaline as leads

• Replacing the amine with larger alkyl substituents yielded selectivity for adrenergic β-receptors over α-receptors

Drug Modification: Addition of substituents

• Adding an extra substituent can create an additional drug–receptor interaction

Drug Modification: Extension/contraction

• Ring extension or contraction can adjust the relative positions of binding groups

• This helps to improve overlap with binding regions

Drug Modification: Simplification of the structure

• Remove non-essential parts; simplify carbon skeleton; remove non-critical chiral centers

• Example comparisons: Morphine vs Pethidine (illustrative)

Drug Modification: Rigidification of the structure

• Leads are often flexible and can bind multiple receptors via different conformations

• Rigidification reduces conformational freedom to limit off-target binding

• Can increase potency and selectivity

Prodrugs to improve membrane permeability

• Parkinson’s disease example: Levodopa is a prodrug of dopamine; it is recognized by carrier proteins to cross membranes; once inside cells, it is converted to dopamine

Prodrugs to improve selectivity

• Capecitabine: a prodrug of 5-fluorouracil (5-FU) with metabolic activation in multiple steps to localize activation at tumor sites:

  • Oral adsorption

  • Hydrolysis in the liver

  • Decarboxylation (–CO₂)

  • Oxidative deamination in liver and tumor

  • Conversion to 5-FU by thymidine phosphorylase in tumor

• Result: Improved selectivity for tumor tissue

Introduction: Lipinski's “Rule” of Five

• A rule of thumb to evaluate drug-likeness for oral activity in humans

• Notes: It predicts pharmacokinetic properties (ADME) but does not guarantee pharmacological activity

• Lipinski’s rule focuses on properties relevant to oral bioavailability

Lipinski's Rule of Five

• Generally, an orally active drug fits at least three of the following:

  • Molecular weight under $500 \, \mathrm{g\,mol^{-1}}$

  • Not more than five hydrogen bond donors

  • Not more than ten hydrogen bond acceptors

  • LogP < 5

• Rationale: Not too big; not too soluble or insoluble

Example: Lipinski's Rule of Five

• Example compound with values: MW = $193.2\, \mathrm{g\,mol^{-1}}$; H-bond donors = 1; H-bond acceptors = 3; LogP = 1.86

• All values satisfy Lipinski criteria for an orally active drug

Introduction: Veber’s “Rules”

• Additional rules for oral bioavailability:

  • Ten or fewer rotatable bonds

  • Polar surface area (PSA) ≤ $140\, \text{Å}^2$

  • Twelve or fewer total hydrogen bonds (donors + acceptors)

• Example values often cited: H-bond donors = 1; H-bond acceptors = 3; total H-bonds = 4; Rotatable bonds = 5; PSA = 30.5 Ų

Example: Lipinski's Rule of Five & Veber’s “Rule”

• Doxorubicin (example):

  • MW = $543\, \mathrm{g\,mol^{-1}}$ (exceeds 500)

  • LogP = -1.7

  • H-bond donors = 7 (>5)

  • H-bond acceptors = 12 (>10)

  • Total H-bonds = 19 (>12)

  • Rotatable bonds = 13 (>10)

  • PSA = 206 Ų (> 140)

• Gate: All Lipinski/Veber criteria are exceeded for Doxorubicin except the LogP value; it is administered by intravenous infusion

Summary

• Introduced the drug discovery process: choosing a disease, selecting a target, and identifying lead compounds

• Discussed how drugs interact with the body and the importance of chemical properties in determining success

• Explained Lipinski’s Rule of Five and Veber’s Rules for predicting oral bioavailability

• Explored strategies to optimise drug design, including substituent changes, rigidification, and prodrug development

• Covered common drug–target interactions such as hydrogen bonding, ionic bonding, hydrophobic effects, and Van der Waals forces

• Used real-world examples (e.g., Levodopa, Capecitabine, Doxorubicin) to illustrate how medicinal chemistry principles are applied in practice