Intro to Drugs & Physiochemical Basis of Drug Action

• What are physiochemical properties?

  1. the physical & chemical properties of a molecule
  2. the 3D shape & electrostatic positions of a molecule
• Physiochemical properties define the molecular form.
• Molecular form controls the molecular function.
• Physiochemical properties explain molecular interactions by:

  1. how a molecule interacts with & changes its target molecule (protein target)
  2. how a molecule interacts with water molecules (soluble in water)
  3. how a molecule interacts with lipid membranes to determine if it can cross or not (lipophilicity)
• Drugs capable of passing the BBB generally are lipophilic molecules with at least one tertiary amine functional group.
• The 6 elements of life are: Hydrogen, Carbon, Oxygen, Nitrogen, Phosphorus, & Sulfur.
• The important takeaways from Coulomb's Law:

  1. the size of charge determines strength of force
  2. the force between charges is related to the distance between them
  3. small changes in distance has a huge effect on the force (because of the inverse square relationship)
• Coulomb's Law equation answers the question of how charges optimally interact.
• The optimal distance between 2 species is at the lowest energy state or "happy point".
• The molecular shape is defined by electron clouds.
• Electrostatics determine drug binding to a protein, which determines the shape of the drug molecule.
• Atomic number


  Number of protons
• Orbitals


  Separate electrons on different energy levels.

  Or, the region of space where 0, 1, or 2 electrons of a given energy can be found.
• Octet Rule


  2nd row elements need to have 8 e- to fill all 4 orbitals: (1s) 2s, 2px, 2py, & 2pz.
• As more electrons are drawn to the nucleus, the electrostatics dictate how the orbitals are organized.
• The number of bonds an atom needs to fill its shell (complete its octet) is determined by the atoms number of valence electrons.
• Valence electrons are the electrons available for bonding.
• At low energy, atoms need to:

  1. Fill orbitals
  2. Close their octets
• How do we recalculate orbitals to minimize electrostatic repulsion between electrons in orbitals upon bonding?

  The valence orbitals are hybridized.
• The overall form (shape) of molecules is therefore determined by the hybrid orbital used in bonding.
• The geometry of an sp3 atom is tetrahedral.
• Tetrahedron


  The answer to how to get 4 things that hate each other connected through a central point as far away from each pother as possible in 3 dimensions.
• The geometry of an sp2 atom is trigonal planar.
• Trigonal Planar


  The answer to how to get 3 things that hate each other connected through a central point as far away from each other as possible in 2 dimensions.
• • The presence of the non-hybridized 2pz orbital on both carbon atoms is the basis to the double bond (alkene).
  • Double bonds = sp2 hybridized atoms
• Nitrogen

  Atomic # = 7

  Valence e- = 5

  How many bonds? = 3
• Carbon

  Atomic # = 6

  Valence e- = 4

  How many bonds? = 4
• Oxygen

  Atomic # = 8

  Valence e- = 6

  How many bonds? = 2
• You can determine the hybridization of an atom by counting how many bonding sites it has (and -1 for the exponent).
• Imbalances in electrostatic charge can always exist and are always higher in energy than neutral.
• Ions


  • Atoms or molecules that are charged
  • Exist because there are too many (cation) or too few (anion) electrons to match the number of positive protons in an atom nucleus
  • Referred to as having a formal charge
  • More reactive & more likely to make bonds
• Anions occur when atom takes an electron without making a bond (hydroxide).
• Cations occur when an atom starts sharing one of its electrons to make a bond (hydronium).
• Atoms like carbon are too high in energy to be likely found in biological settings or drug molecules.
• The geometry of an sp atom is linear.
• Salts


  Made from the transfer of an electron between an element that needs to lose an electron to get a closed electron shell (Na+, K+) & an atom needing one additional electron to close its shell (Cl-)
• Amine salts


  • Made from the cation on a N of an amine (ammonium) & an anionic counter ion (H+Cl- or H+Br-).
  • Often forms through an acid/base reaction with the N of the amine acting as a base with a strong acid.

  
• 1. The electrons in covalent bonds are shared but not equally.
  2. Bonds can be sigma ($\sigma$) or pi ($\pi$)
• Sigma bond = single

  Pi bond = double
• The major determinant in defining the nature of covalent bonds is electronegativity.