Interdisciplinary design of bioactive small molecules: structure–activity relationships, pharmacokinetics, lead discovery and optimisation. Substrate of pharmaceutical R&D.
medicinal-chemistry
Lipinski's rule of five
Empirical heuristic for oral drug-likeness: MW ≤ 500, log P ≤ 5, HBD ≤ 5, HBA ≤ 10. Compounds violating more than one rule have markedly…
Structure–activity relationship (SAR)
Systematic correlation of structural modifications with biological potency. Quantitative SAR (QSAR) regresses log(1/IC50) on molecular…
Lead compound
Chemical starting point with demonstrated biological activity on the target (IC₅₀ typically 100 nM–10 μM) that is iteratively optimised for…
Pharmacokinetics (ADME)
Absorption, Distribution, Metabolism, Excretion — quantified by C_max, T_max, AUC, half-life t_{1/2}, volume of distribution V_d, clearance…
Drug–target interaction
Binding described by K_d = k_off/k_on; residence time t_res = 1/k_off increasingly recognised as better potency predictor than K_d alone.…
Prodrug strategy
Administered pharmacologically-inactive precursor metabolically converted to the active drug in vivo. Used to improve solubility…
Bioisostere
Functional-group substitution preserving key interactions (volume, lipophilicity, H-bonding) while altering metabolism or patent space.…
Fragment-based drug design
Screens small (MW<300) 'fragments' at high concentration via NMR/SPR/X-ray; hits are fused or grown into lead compounds. Delivered e.g.…
Structure-based drug design & docking
Use of protein 3D-structure (X-ray / cryo-EM / AlphaFold) to design ligand binding. Docking algorithms (AutoDock / Glide / GOLD)…
Proteolysis-targeting chimera (PROTAC)
Crews-Deshaies 2001 PROTAC: heterobifunctional small-molecule recruits E3-ubiquitin-ligase to target-protein → ubiquitination +…
Peptide therapeutic design
Peptides occupy chemical-space between small-molecules and proteins (1-50 residues, 0.5-5 kDa). Synthetic strategies: Fmoc-SPPS,…
AI drug discovery (AlphaFold + diffusion-models)
Jumper-Hassabis 2021 AlphaFold-2 cracks protein-folding 50-year challenge (Nobel 2024). AlphaFold-3 (2024) extends to ligand /…
Hill-Langmuir equation
Hill 1910 cooperative binding: theta = [L]^n / (Kd^n + [L]^n); n = Hill coefficient; n>1 positive cooperativity (hemoglobin n~2.8), n<1…
Rule of 5 (Lipinski 1997)
C Lipinski 1997 rule of five: MW<=500, log P<=5, HBD<=5, HBA<=10 for drug-like absorption; >85% oral drugs comply; modern beyond-Ro5…
SBDD (Blundell 1980s)
T Blundell 1980s + Wlodawer HIV-protease 1989: X-ray structure-guided inhibitor design; saquinavir 1995 first SBDD-launched drug; modern…
ADMET (Vrijhof 1997)
Vrijhof 1997 ADMET: Absorption + Distribution + Metabolism + Excretion + Toxicity; in-silico models (e.g. CYP-450) predict 80% of attrition…
AlphaFold drug discovery (2021)
DeepMind 2021 AlphaFold-2 atomic-resolution structure prediction; Insilico-Medicine 2022 first AI-discovered + AI-designed drug Phase-1;…
mAbs (Koehler-Milstein 1975)
G Koehler-C Milstein 1975 (Nobel 1984) hybridoma technology; humanized + fully-human Abs; modern bispecific + ADC + CAR-T derivatives.
Lock-and-key (Fischer 1894)
E Fischer 1894 (Nobel 1902) lock-and-key; modern induced-fit + conformational-selection + cryo-EM ensemble drug-design.
Ro5 (Lipinski 1997)
C Lipinski 1997 rule-of-five; modern bRo5 oral-bioavailability + Veber + PROTACs beyond classical drug-space.
Hammett σρ (1937)
L Hammett 1937 linear-free-energy log(k/k0)=σρ; modern QSAR foundation + Taft + Hansch hydrophobic + Topliss tree.
Free-Wilson QSAR (1964)
S Free-J Wilson 1964 additive substituent-contribution QSAR; modern matched-molecular-pairs analysis + 3D-QSAR.
AlphaFold-drug (2022)
Jumper 2021 AlphaFold2 + 2022 PostEra antiviral; modern structure-based-drug-design 200M predicted protein structures.
ADMET (van de Waterbeemd 2001)
H van de Waterbeemd-E Gifford 2001 ADMET in silico prediction; modern pkCSM + SwissADME + DeepPK ML 2024.