Medicinal Chemistry Compendium PDF

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Wiktor Szymanski

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medicinal chemistry chemical properties biological properties chemistry

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This document is a compendium of medicinal chemistry definitions, equations, rules, and interactions. It covers topics such as bioisosteres, conformations, configurations, and covalent inhibitors. It's a valuable resource for medicinal chemistry students and professionals.

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Medicinal Chemistry Compendium, Wiktor Szymanski, GRIP, FSE RUG, Version1 1. Definitions Bioisosteres Chemical substituents with similar physical or chemical properties which produce similar biological properties Conformation (of a Any one of the inf...

Medicinal Chemistry Compendium, Wiktor Szymanski, GRIP, FSE RUG, Version1 1. Definitions Bioisosteres Chemical substituents with similar physical or chemical properties which produce similar biological properties Conformation (of a Any one of the infinite number of possible spatial arrangements of molecule) atoms in a molecule that result from rotation of its constituent groups of atoms about single bonds (without breaking those bonds). Configuration (of a Permanent geometry of a molecule that results from the spatial molecule) arrangement of its bonds. Changing configuration requires the breaking of sigma bonds. Examples of configuration: R, S, E, Z, etc. Coulomb Law Equation that calculates the magnitude of the force F between two point charges, separated by a distance r. Covalent inhibitor Inhibitors that bind to their target in two steps, starting with equilibrium bond formation, and ending with covalent bond formation. Craig plot A plot of two substituent parameters (e.g. Hansch-Fujita π constant and Hammet sigma constant) used in rational drug design Dielectric constant A constant that describes the the ease by which a dielectric medium may be polarized. It correleates with the polarity of the solvent Dipole moment A measure of the separation of positive and negative electrical charges within a system Electronegativity A measure of the tendency of an atom to attract a bonding pair of electrons H2L (Hit-to-lead) A stage in early drug discovery where small molecule hits from a high throughput screen (HTS) are evaluated and undergo limited optimization to identify promising lead compounds. Halogen bond Electrostatic interaction between an electrophilic region associated with a halogen atom in a molecular entity and a nucleophilic region in another, or the same, molecular entity. Hammett constant σ A constant that quantifies the electronic properties of a substituent (electron donating/withdrawing) Hammett constants Constants that describe the electronic properties of the substituent (modified) σ+, σ- (electron donating/withdrawing), taking into the consideration its ability to stabilize the positive (σ+) or negative (σ-) charge through conjugation. Hansch equation Equation which relates biological activity of a compound to a number of different molecular parameters. Hansch-Fujita constant A constant that quantifies the hydrophobicity a substituent Henderson-Hasselbalch Equation which relates the ratio of concentrations of protonated and equation deprotonated forms of a molecule to its pKa and the pH of the solution. Hydrogen bond Electrostatic interaction between an atom with a basic lone pair of electrons and a hydrogen atom that has been partially stripped of its electrons Medicinal Chemistry Compendium, Wiktor Szymanski, GRIP, FSE RUG, Version1 Hydrophobic Non-covalent forces where nonpolar species tend to cluster in water in interactions order to decrease the overall interfacial area between the hydrophobic species and water. Intermolecular forces Relatively weak (non-covalent) interactions between molecules, such as (interactions) hydrogen or halogen bonding, pi-pi interactions, van der Waals interactions. Intramolecular forces Relatively strong interactions that bind atoms together within a molecule: ionic and covalent bonds. Isomers Two molecules with the same formula but a different arrangement of atoms in the molecule and different properties. London dispersion Intermolecular interactions between induced dipoles forces Molecular electrostatic Graphical representation of interaction energy between the charge potential map distribution of a molecule and a unit positive charge. Pharmacophore An abstract description of molecular features that are necessary for molecular recognition of a ligand by a biological macromolecule. Polar Surface Area Surface sum over all polar atoms in a molecule, primarily oxygen and nitrogen, also including their attached hydrogen atoms. Prodrug A pharmacologically inactive compound that, after intake, is metabolized into a pharmacologically active drug QSAR Quantitative Structure-Activity Relationships, a mathematical model that quantitatively relates a quantitative numerical measure of chemical structure to a biological effect. Resonance structures A set of two or more Lewis structures that collectively describe the electronic bonding of a molecule Rotatable bond Any single non-ring bond, attached to a non-terminal, non-hydrogen atom. Excluded are amide C-N bonds and ester single C-O bonds because of their high rotational energy barrier. SAR Structure-Activity Relationships, relationship between the chemical structure of a molecule and its biological activity. Taft steric factor Es A constant that quantifies the steric properties of a substituent Topliss scheme A simple decision tree (scheme) used by medicinal chemists to decide the substituents to be evaluated in order to avoid having to synthesize all possible analogues. Transition state A drug that resembles not the substrate or product, but the transition analogue state of an enzyme that it inhibits. van der Waals A group of intermolecular interactions that includes dipole-ion, dipole- interactions dipole, induced dipole-dipole and induced dipole – induced dipole interactions Medicinal Chemistry Compendium, Wiktor Szymanski, GRIP, FSE RUG, Version1 2. Equations 2.1. Coulomb Law 2.2. Definition of pKa 2.3. Henderson-Hasselbalch equation + pH = -log[H ] - defines the acidity of the solution [𝑯𝑯𝐀𝐀] pKa – defines the strength of an acid = 10𝒑𝒑𝒑𝒑𝒑𝒑−𝒑𝒑𝒑𝒑 [𝑨𝑨 ] − pKa of an acid is the pH at which half of the acid molecules are deprotonated [AH] = [A-] - pH = pKa: protonated = deprotonated [HA] = [A ] - pH < pKa: more protonated form [HA] > [A ] - pH > pKa: more deprotonated form [HA] < [A ] |pKa-pH| How much more? 10 2.4. Typical Hansch equation Medicinal Chemistry Compendium, Wiktor Szymanski, GRIP, FSE RUG, Version1 3. Rules 3.1. The Lipinski Rule of 5 (Christopher A. Lipinski, 1997); rule of thumb to evaluate drug-likeness or determine if a chemical compound with a certain pharmacological or biological activity has chemical properties and physical properties that would likely make it an orally active drug in humans. - No more than 5 hydrogen bond donors - No more than 10 hydrogen bond acceptors - A molecular mass less than 500 Da - A calculated octanol-water partition coefficient (cLog P) that does not exceed 5 (and be around 2 for crossing the blood-brain barrier, BBB). 3.2. The Verber Rules (Daniel Veber, 2002) question the 500Da cutoff and and state: - 10 or fewer rotatable bonds and - Polar surface area no greater than 140 Å2 (for crossing the BBB: 90 Å2)

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