Outline
I Targets in Biology and Medicine
II. Chemical Space
III. Relevant Physicochemical Properties
IV. Case Study V. Summary
Targets in Biology and Medicine
• Enzymes
• Proteins
• Nucleic acids
• Channels
• Membranes
• Miscellaneous
Knowledge discovery vs drug discovery
• Ligand vs drug
• Chemical tool to modulate each known protein
• In vitro vs in vivo
6 Druggable target • A B C D E
Proteins
• Proteins: 20 amino acids, ~300 residues/protein, 20300 or 10390 possible combinations
• Natural proteins are a very select group
• Genomics and proteomics: identify molecular targets for therapeutic intervention (less than 500 proteins are targeted by drugs: very small percentage)
Biological Tools for investigating biological function
• – Protein-specific antibodies
• – Engineered recombinant proteins
• – Gene knockouts
• – Gene knockins
• – RNA Interference
Advantages and Limitations
• Cheaper and more efficient to develop than small molecule chemical tools
• Specific: Can selectively delete or silence the expression of almost any gene in model organisms (fruitfly, zebrafish, mouse)
• Not useful in investigation of dynamic, reversible, and temporal elements of protein function 10 II. Chemical Space Chemicals can be characterized by a wide range of ‘descriptors’, such as their molecular mass, lipophilicity (their affinity for a lipid environment) and topological features. ‘Chemical space’ is a term often used in place of ‘multi-dimensional descriptor space’: it is a region defined by a particular choice of descriptors and the limits placed on them. It can also be described as the total descriptor space that encompasses all the small carbon-based molecules that could in principle be created
Chemical Space
• “Chemical space is for all practical purposes infinite and limited only by the chemist’s imagination.”
• Hexane (C6) has 1029 possibilities using 150 substituents.
• Chemography: using descriptors to map chemical space – 2 major categories – physicochemical properties and topological descriptors. 12 Chemical Tools
• Chemical genetics or genomics: using small molecules (chemical tools) to probe biological systems
• Natural products: small numbers, rich chemical diversity
• Chemical tools can be used in target validation
• Selectivity, toxicity, and other considerations
Biologically relevant chemical space
Those parts of chemical space in which biologically active compounds reside. How do we best direct our efforts towards regions of chemical space that are most likely to contain molecules with useful biological activity?
Chemical space
• Biologically-relevant chemical space
• Pharmacological space
• Topological/Geometrical Shape
• Charge on the molecular surface or electrostatic potential
Compound vs Drug
• Compounds (Chemical space, infinite and limited only by the chemist’s imagination).
• Biologically active compound (subset occupying biologically-relevant chemical space, more criteria).
• Drug (Even more criteria including ADMET, bioavailability, pharmacokinetics, in vivo activity). 20 III. Relevant Physicochemical Properties Passive Diffusion (as opposed to active transport) A. Molecular Weight
B. Solubility
C. Ionization
D. Log P
Molecular Weight
• MS
• Elemental Analysis
Solubility & C. Ionization
• Functional groups
• pH
• Ionized vs unionized
Log P
Important factors for oral drugs include: -Dissolution -Absorption These affect bioavailability.
Cell Membranes
• Cell membranes are bilayers containing both hydrophilic and hydrophobic groups. Proteins are also embedded in the membrane. Drugs require certain physiochemical properties in order to permeate through.
Log P values The optimum values for targeting CNS penetration: Log P = 2 +/- 0.7 Oral absorption: Log P = 1.8 Intestinal absorption: Log P =1.35 Colonic absorption: Log P = 1.32 Sublingual absorption: Log P = 5.5 26
Lipinski’s Rule of Five
• Examination of orally administered drugs
• Predict oral bioavailability
• A) Molecular mass of less than 500 daltons
• B) Log p of less than 5
• C) Less than 5 hydrogen bond donors
• D) Less than 10 hydrogen bond acceptors
Drug-like properties
For small molecule drugs, molecular size, hydrogen bonding capability and lipophilicity in terms of log P (or log D) should fall within a certain range to be an oral drug candidate.
IV. Case Study
• Alzheimer’s Disease
• Ideal drug will be bioavailable in the CNS after oral administration. 32 FDA Approved AD Drugs
• Anticholinesterases – Tacrine (Cognex®) – Donezepil (Aricept®) – Rivastigmine (Exelon®) – Galantamine (Reminyl®)
• NMDA-R antagonist – Memantine (Namenda®) A. Adejare 17 33 P
AD pathology
• Formation Of Amyloid Plaques – Overproduction of Aβ peptide – Aβ40/42 (~90%/10%) – Aβ42 more hydrophobic – Plaque formation causes inflammatory response and altered ionic homeostasis
V. Summary
– Chemical Space
– Biologically Relevant Chemical Space
– Pharmacological Space
– Lipinski’s Rule of Five
– Pharmaceutical Profiling
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