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Prof. Gustavo Pozza Silveira Introduo a Qumica Medicinal
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INTRODUO A QUMICA
MEDICINAL
Prof. Gustavo Pozza Silveira
gustavo.silveira@iq.ufrgs.br
Sala 201A Bloco E
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Prof. Gustavo Pozza Silveira Introduo a Qumica Medicinal
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Enzimas catalisador natural da vida.

Receptores sistama de comunicao natural da vida.
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Prof. Gustavo Pozza Silveira Introduo a Qumica Medicinal
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Estrutura e funo de enzimas

Proteinas globulares agem como catalisadores do corpo.
Aumentam a velocidade reacional para que a mesma atinja o equilbrio.
Diminuem a energia de ativao reacional.

Examplo:
LDH = Lactate dehydrogenase (enzyme)
NADH
2
= Nicotinamide adenosine dinucleotide (reducing agent & cofactor)
Pyruvic acid = Substrate
LDH
Pyruvic acid
Lactic acid
H
3
C
C
C
O
O
HO
C
O
C H
3
C
H
NADH
2
NAD
+
+ +
OH
OH
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Prof. Gustavo Pozza Silveira Introduo a Qumica Medicinal
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Diminui a energia de ativao de uma reao:
Act.
energy
Transition state
SEM ENZIMA
Product
Starting
material
Energia
COM ENZIMA
Product
Starting
material
Energia
G
New
transition
state
G
Act.
energy
Enzimas diminuem a energia de ativao reacional, mas DG
permanece o mesmo.

Estrutura e funo de enzimas
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Mtodos de catlise enzimtica
Promovem uma superfcie reacional (o stio ativo)

Promovem o ambiente adequado para reao environment (hidrofbico).

Aproximam os reagentes.

Posicionam reagentes corretamente para reao (confrmeros).

Enfraquecem ligaes nos reagentes.

Promovem catlise cida / basica.

Intensificam grupos nucleoflicos.
Estrutura e funcionamento de enzimas
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Sitio ativo
Cavidades ou hidrofbicas na superfcie enzimtica.

Aceitam reagentes (substratos e cofatores)

Contem aminocidos que:
- Ligam-se a reagentes (substratos and cofactores).
- Catalisam a reao.
ENZYME
Active site
Active site
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Notas:

Stio ativo est prximo do formato correto para interao com o substrato.
Ligao altera o formato da enzima (prenchimento induzido).
Fora de ligao com o substrato aumentada devido a induo.
Ligao envolve foras intermoleculares entre grupos funcionais do substrato e
do stio ativo.
Prenchimento induzido.

Induced fit
Substrate
S
Ligao do substrato
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Ligao do substrato
Ionic
H-bonding
van der Waals

Foras ligantes
Examplo

S
Enzyme
Active site
vdw
interaction
ionic
bond
H-bond
Phe
Ser
O
H
Asp
CO
2

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Prof. Gustavo Pozza Silveira Introduo a Qumica Medicinal
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H
3
C
C
C
O
O
O
Ionic
H-bonding
van der Waals
Examplo - Binding of pyruvic acid in LDH
H-Bond
Possible interactions vdw-interactions
O
H
H
3
N
H
3
C
C
C
O
O
O
Ionic bond
H-Bond
H
3
C
C
C
O
O
O
van der Waals
H
3
C
C
C
O
O
O
Ionic
H
3
C
C
C
O
O
O
Ligao do substrato
Foras ligantes
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Prof. Gustavo Pozza Silveira Introduo a Qumica Medicinal
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Lactate dehydrogenase is a safety valve in our pipeline of energy production.
Most of the time, our cells break down glucose completely, releasing the carbon
atoms as carbon dioxide and the hydrogen atoms as water. This requires a lot of
oxygen. If the flow of oxygen is not sufficient, however, the pipeline of energy
production gets stopped up at the end of glycolysis. Lactate dehydrogenase is
the way that cells solve this problem, at least temporarily.
During sprints or other over-exertions, there isn't enough oxygen to go around. In
this case, our cells use glycolysis as their primary source of energy, As part of
glycolysis, hydrogen from glucose is placed on NAD+ to form NADH. Normally,
these hydrogen atoms are then transferred to oxygen to form water. If oxygen
isn't available, the NADH builds up and there isn't enough NAD+ to continue
using glycolysis to make ATP. That's where lactate dehydrogenase steps in: it
combines pyruvate and NADH, producing lactic acid and NAD+. The NAD+ can
then be recycled to do another round of glycolysis.
Lactato dehydrogenase
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Lactato dehydrogenase
Ligantes: NADH (cofator) e cido pirvico (substato).
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Lactato dehydrogenase
Ligantes: NADH (cofator) e cido pirvico (substato).
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Induo do molde correto Stio ativo alterado para maximizar ligaes
intermoleculares.
Foras de ligao
Intermolecular bonds not optimum
length for maximum bonding

Intermolecular bond lengths optimised
Susceptible bonds in substrate
strained
Susceptible bonds in substrate more
easily broken

S
Phe
Ser
O
H
Asp
CO
2

Induced
fit
S
Phe
Ser
O
H
Asp
CO
2

Ligao do substrato
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Prof. Gustavo Pozza Silveira Introduo a Qumica Medicinal
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Ligao do substrato
Example - Binding of pyruvic acid in LDH
O
H
H
3
N
H
3
C
C
C
O
O
O
O
O
O
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Prof. Gustavo Pozza Silveira Introduo a Qumica Medicinal
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Example - Binding of pyruvic acid in LDH
O
H
H
3
N
p bond
weakened
H
3
C
C
C
O
O
O
Ligao do substrato
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Prof. Gustavo Pozza Silveira Introduo a Qumica Medicinal
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Mecanismo de catlise
Histidine

Catlise cido/base
Residos nucleoflicos
N
NH
+H
-H N
NH
H
Non-ionised
Acts as a basic catalyst
(proton 'sink')
Ionised
Acts as an acid catalyst
(proton source)
H
3
N CO
2
OH
H
L-Serine
H
3
N CO
2
SH
H
L-Cysteine
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Prof. Gustavo Pozza Silveira Introduo a Qumica Medicinal
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Mecanismo de catlise
O H
S e r
X
Substrate
O
Ser
H
2
O
O H
Ser
H O
Product
Serina agindo como nuclefilo
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Prof. Gustavo Pozza Silveira Introduo a Qumica Medicinal
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Mechanism for chymotrypsin
Catalytic triad of serine, histidine and aspartate
Chymotrypsin
N N
O H
H
O O
S e r
H i s A s p
..
:
:
Mecanismo de catlise
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Prof. Gustavo Pozza Silveira Introduo a Qumica Medicinal
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Mechanism for chymotrypsin
P r o t e i n N H
C
O
P r o t e i n
: :
Chymotrypsin
N N
O H
H
O O
S e r
H i s A s p
..
:
:
Mecanismo de catlise
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Prof. Gustavo Pozza Silveira Introduo a Qumica Medicinal
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Mechanism for chymotrypsin
O
Protein NH C
O
Protein
: :
:
Chymotrypsin
N N
H
H
O O
S e r
H i s A s p
:
:
Mecanismo de catlise
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Prof. Gustavo Pozza Silveira Introduo a Qumica Medicinal
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Mechanism for chymotrypsin
N
O
Protein NH C
O
Protein
: :
:
:
H
Chymotrypsin
N
H
O O
S e r
H i s A s p
: :
Mecanismo de catlise
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Prof. Gustavo Pozza Silveira Introduo a Qumica Medicinal
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Mechanism for chymotrypsin
O
C
:
O Protein
:
:
H
O
H
:
:
Chymotrypsin
N N
H
O O
S e r
H i s A s p
:
:
:
Mecanismo de catlise
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Prof. Gustavo Pozza Silveira Introduo a Qumica Medicinal
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Mechanism for chymotrypsin
O
H
O
C
O
Protein
: :
:
H
Chymotrypsin
N N
H
O O
S e r
H i s A s p
:
:
:
Mecanismo de catlise
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Prof. Gustavo Pozza Silveira Introduo a Qumica Medicinal
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Mechanism for chymotrypsin
:
N
O
O
C
O
Protein
: :
:
H
:
:
H
Chymotrypsin
N
H
O O
S e r
H i s A s p
: :
Mecanismo de catlise
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Prof. Gustavo Pozza Silveira Introduo a Qumica Medicinal
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Mechanism for chymotrypsin
OH
C
O
Protein
: :
Chymotrypsin
N N
O H
H
O O
S e r
H i s A s p
..
:
:
Mecanismo de catlise
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Prof. Gustavo Pozza Silveira Introduo a Qumica Medicinal
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Mechanism for chymotrypsin
N N
OH
C
protein
H
O O
Ser His Asp
OH
O
:
:
..
N N
O H
protein NH
C
O
protein
H
O O
Ser His Asp
:
..
:
:
:
N N
O H
protein NH
C
O
protein
H
O O
Ser His Asp
:
:
:
:
..
N N
O
protein NH
C
O
protein
H
O O
Ser His Asp
H
:
:
:
..
:
N N
O
C
O
H
O O
Ser His Asp
:
: :
:
:
protein
O
H H
:
:
N N
O
C
O
protein
H
O O
Ser His Asp
O
H
H
: :
:
: :
..
..
N N
O
C
O
protein
H
O O
Ser His Asp
OH
H
: :
: :
..
..
..
Mecanismos de catlise
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Processo completo de catlise enzimtica
S
E
ES
P
E
EP
P
E
E + P
E
S
E + S
E
Notes:

Interas lingantes devem ser fortes o suficiente para manter o substrato preso
o tempo necessrio para que a reao ocorra.
Porm, as interaes devem ser fracas o suficiente para permitir que o substrato
deixe o stio ativo aps a catlise.
Esse antagonismo deve ser seriamente levado em considerao!
O planejamento de molculas que liguem-se fortemente ao stio ativo poder
bloque-lo permanentemente!
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Many enzymes are regulated by agents within the cell
Regulation may enhance or inhibit the enzyme
The products of some enzymes may act as inhibitors
Usually bind to a binding site called an allosteric binding site
Example
Phosphorylase a
Glucose-1-phosphate
HO
O
H
H
HO
H
O
OH
H
H
OH
P
OH
O
HO
O
O
H
H
HO
H
OH
OH
H
H
OH
Glycogen
n
N
N
N
N
NH
2
O
OH OH
H H
H H
O P O
O
O
AMP
Regulando o funcionamento de enzimas
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ACTIVE SITE
(open)
ENZYME Enzyme
Inhibitor binds reversibly to an allosteric binding site
Intermolecular bonds are formed
Induced fit alters the shape of the enzyme
Active site is distorted and is not recognised by the substrate
Increasing substrate concentration does not reverse inhibition
Inhibitor is not similar in structure to the substrate
Allosteric
binding site
Active site
(open)
ENZYME
Enzyme
Induced
fit
Active site
unrecognisable
Allosteric
inhibitor
Regulando o funcionamento de enzimas
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Notes

Enzymes with allosteric sites are often at the start of a biosynthetic pathway
Enzyme is controlled by the final product of the pathway
Final product binds to the allosteric site and switches off enzyme

P
P P
Biosynthetic pathway
Feedback control Inhibition
P S
(open)
ENZYME
Enzyme
Regulando o funcionamento de enzimas
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Forma ativa Forma inativa - alstero
Some bacteria obtain most of their energy by conversion of glucose into
lactose. This process is called fermentation. The bacterial lactose
dehydrogenase shown here is an allosteric enzyme. Binding of fructose 1,6-
bisphosphate, one of the molecules formed in the early steps of glycolysis,
causes the enzyme to change into an active shape.
ALSTEROS LACTATO DEHYDROGENASE
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ALSTEROS LACTATO DEHYDROGENASE
Cloranfenicol liga-se na poro que seria ocupada pela frutose 1,6-bifosfato
impedindo a formao alostrica que leva a forma ativa da enzima.
The protozoan parasites that cause malaria are thought to rely on glycolysis
for most of their energy during part of their cycle of infection.
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Protein
kinase
Cell
Regulando o funcionamento de enzimas
External signals can regulate the activity of enzymes (e.g. neurotransmitters or
hormones)
Chemical messenger initiates a signal cascade which activates enzymes called
protein kinases
Protein kinases phosphorylate target enzymes to affect activity

Example

Adrenaline
Signal
cascade
Phosphorylase b
(inactive)
Phosphorylase a
(active)
Glycogen Glucose-1-phosphate