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New and old drugs
Drug design and discovery
Secondary stage rash
in syphylis on the
palms of the hands.
Bacteria Treponema
pallidum
Old drugs: treated with
arsenic and mercury
Adverse side effects:
inflammation of the gums,
destruction of the teeth and jaws,
and organ damage
Beta-lactam antibiotics
1941 WWII
Large scale production of
penicillin
New drugs: penicillin
1928 Alexander Fleming
Beta-lactamase
Beta-lactam antibiotics
Bacteria develop
drug resistance
Until 2003, more than half of
all commercially available
antibiotics in use were
β-lactam antibiotics
Clavulanic acid
Beta-lactamase inhibitor
The peptidoglycan (or murein) layer in
the bacterial cell wall is a crystal lattice
structure formed from linear chains of
two alternating amino sugars, namely
N-acetylglucosamine ( NAG) and Nacetylmuramic acid (NAM).
Attached to the NAM is an oligopeptide
chain of three to five amino acids. The
peptide chain can be cross-linked to
the peptide chain of another strand
forming the 3D mesh-like layer.
PBP – Penicillin binding proteins
(DA-DA-transpeptidase) cleave the terminal
D-Ala to perform the crosslinking.
Penicillin binds to transpeptidase
The cell wall growth is stoped
Lab2-peptides
Penicillin mimics the D-alanyl-D-alanine (DA-DA)
residues that normally bind to the active site in the
transpeptidase enzyme:
-similar structure
-similar functional groups
-better binding than DA-DA, irreversible binding
Penicillin biosynthesis
Company Pfizer engineered production of
gluconic acid and vitamin C using deep-tank
fermentation and extended it to penicillin.
The first penicillin plant was built in 1944 with
several 7,500 gallon tanks. In 1942, there was
enough drug for ten doses, by 1945 there was
enough to treat 646 billion.
Beta-lactamase secreted by bacteria destroys the antibiotic active site structure
Ampicillin
Amoxicillin
Ampicillin isn't well absorbed with a bioavailability of 40%.
Amoxicillin, was designed this time by changing the benzene to a phenol. The addition
of the hydroxyl group (-OH) now increases the bioavailability of Amoxicillin to 95% and
allow it to be taken orally.
Cephalosporins are more stable
(due to a double bond) to the
action of beta-lactamase that
destroy the antibiotic activity.
Structural differences
between penicillin (1)
and cephalosporins (2)
D-alanyl-D-alanine carboxypeptidase/
transpeptidase
Penicillin 
Atomic-scale simulations of reactive oxygen plasma species
interacting with bacterial cell walls
M Yusupov et al 2012 New J. Phys. 14 093043
peptidoglycan structure to model the gram-positive
bacterium Staphylococcus aureus murein interaction with O3,
O2 and O atoms
One phospholipid unit interacting with an OH
radical at the glycerol group (left), and zoomed
pictures of the reaction evolution leading to
breaking of a C-C bond (hydrolysis)
Helical insertion of peptidoglycan produces
chiral ordering of the bacterial cell wall
Wang et all. PNAS 2012
80% of chronic infections are
related to biofilms
Docking search method
Until 1905 cocaine was used as local
anesthetic in dentistry
Side effects – addiction
1905-1960 Novocaine (Procaine)
Side effects – allergy due to its metabolites
From 1950 Lidocaine with epinephrine
cocaine
epinephrine
I – isoleucine, F –phenylalanine, Y - tyrosine
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