Escolar Documentos
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PRCTICA III.3
MODELAGEM MOLECULAR COM O AUXLIO DO COMPUTADOR
MOLECULAR MODELING WITH THE AID OF A COMPUTER
INTRODUO
Modelos so representaes simplificadas de objetos e fenmenos fsicos
reais. A modelagem consiste na construo e manipulao de modelos com
objetivo
de
compreender
mais
profundamente
as
entidades
por
eles
manipulao
e/ou
representadas.
A
modelagem
molecular
consiste
na
gerao,
grficas
permitem
explorar
aspectos
tridimensionais
de
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H
H
HH
2,8 kcal/ mol
H
H
alternada
HH
eclipsada
CH 3
CH 3
H
H
CH 3
H
CH 3
HH
CH 3
H
H
H
CH 3
sinperiplanar
sinclinal
CH 3
H
H
CH 3
anticlinal
antiperiplanar
ciclopropano
ciclobutano
cicloexano
bote
ciclopentano
cicloexano
cadeira
cicloexano
bote torcido
E= Es + Eb + Ew + Enb
Es - energia de estiramento (ou compresso) de uma ligao,
Eb - energia de deformao angular,
Ew - energia de toro em torno de ligaes, e
Enb - energia de interao no ligante
E=
l
K l (l l 0)
2
Kl - constante de fora
l - comprimento de ligao
l0 - comprimento de ligao livre de tenso
Eb =
K (
)2
K - constante de fora
- ngulo de ligao
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Vw
(1 cos nw )
Vw - constante de fora
w - ngulo torsional
n - periodicidade de Vn
2
E nb = Fr 6 + exp[12(1 )]
Fr - constante de fora
=
r____
r 1* + r 2*
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mdias
grandes,
vrios
mtodos
semi-empricos
foram
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O
2
1
O
0 1 2
3
N+
6
10
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8
O
4
CH2
C
2
H3C
1
O
3
6 +
N
CH2
5
CH3
10
CH3
7
1)
2)
3)
Mova o cursor para a janela de desenho e clique o boto do mouse uma vez.
Um ponto aparecer na tela indicando um tomo de carbono (o carbono o
tipo de tomo padro -default).
4)
Afaste o cursor para direita e clique novamente. Aparece uma linha que
significa uma ligao entre dois carbonos j desenhados.
5)
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6)
7)
8)
9)
10)
11)
12)
Para salvar:
Selecione no menu FILE a opo SAVE. Aparece na tela a caixa de dilogo
SALVAR COMO. Nesta caixa de dilogo selecione o diretrio onde o arquivo
vai ser salvo, escreva o nome do arquivo e selecione o tipo de arquivo. O
PCMODEL capaz de salvar o arquivo em diferentes formatos (PCM, prprio
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14)
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ngulo 2
Conformao
classificao da geometria
(O3 e N6)
A
B
C
10) Localizar os pontos em mximo de energia e preencher tabela 2.
Tabela 2- Dados das conformaes em mximo de energia da Ach
EE
classificao da
Conformao
kcal/mol
geometria (O3 e
ngulo 2
N6)
1
2
3
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#dihd
#dihd 0
#dihd 1
#dihd 2
#dihd 3
.
.
#dihd 35
2
X
X+10
X+20
X+30
.
.
X+350
EE
6,848
6,878
8,548
.
.
.
.
#dihd
O3-N6 (A)
CH3-N6(A)
N6-O8(A)
EE
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mnimo A
2 =
mnimo B
mnimo C
2 =
2 =
Exerccios
1) Fazer o desenho da acetilcolina usando diferentes ferramentas do menu
TOOLS (por exemplo, construa a cadeia de tomos usando a ferramenta
BUILD).
2) Fazer a projeo de Newman da acetilcolina em relao aos tomos
O3,C4,C5,N6.
3) Desenhar a estrutura das seguintes molculas: (observar a estereoqumica)
HO
CH3
H3 C
N
O
CH3
CH3
O -C
N(CH3 ) 3
CH3
O -C
CH 3
O
H
N(CH 3 ) 3
H
C CH3
O C CH3
N(CH3 ) 3
N(CH3 ) 3
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CONCLUSO
A prtica proposta permite ao aluno de Qumica Farmacutica utilizar um
programa de modelagem molecular para desnhar e estudar as conformaes de
uma molcula com atividade biolgica. Introduz o estudante no uso de meios
computacionais no estudo de molculas.
BIBLIOGRAFIA
1- FRHBEIS, H.; KLEIN, R.; WALLMEIER, H. Angew. Chem. Int. Ed. Engl., v. 26,
p. 403-418, 1987.
2- BOYD, D. B.; LIPKOWITZ, K. B. J. Chem. Educ., v. 59, n. 4, p. 269-274, 1982.
3- CANEPA, F. G. ; PAULING, P.; SRUM, H. Nature, v. 210, p. 907-909, 1966.
4- COHEN, N. C. , BLANEY, J. M.; HUMBLET, C.; GUND, P.; BARRY, D. C. J.
Med. Chem., v. 33, n.3, p. 883-894, 1990.
5- COX, P. J. J. Chem. Educ., v. 59, n. 4, p. 275-277, 1982.
6- DOWEYKO, A. M. J. Med. Chem., v. 37, p. 1769-1778, 1994.
7- FERGUSON, D. M.; RABER, D. J. J. Am. Chem. Soc. , v. 111, p. 4371-4378,
1989.
8- HLTJE, H. D.; FOLKERS, G. Molecular Modeling- Basic principles and
applications. NewYork: VHC, 1996. 194 p.
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MATERIAL SUPLEMENTAR
SUMRIO RPIDO DAS FUNES DA BARRA DE MENU DO PCMODEL 7.0
Menu File
Open
L um arquivo a partir do disco
Save
Salva um arquivo para o disco
Save graphic
Salva a imagem grfica para o disco
Print
Imprime a estrutura corrente e a janela de energia
Exit
Sai do PCMODEL
Menu Edit
Draw
Recupera o menu TOOLS
Erase
Apaga todas estruturas
Structure Name Edita ou entra com o nome da estrutura
Hide hidrogens
Faz os hidrognios da estrutura ficarem invisveis, mas
presentes
Epimer
Epimeriza o tomo selecionado atravs da troca de dois
ligantes selecionados
Enantiomer
Reflete a estrutura atravs de um eixo especificado
Remove LP
Remove os pares de eltrons livres
Copy_To_Clipboard
Copia a imagem da estrutura para a memria
Orient_XY
Orienta trs tomos selecionados no plano XY (XZ ou
YZ) com o primeiro tomo
Orient_XZ
na origem, o segundo no eixo e o terceiro no plano
Orient_YZ
Menu View
Control Panel
Carrega a caixa de dilogo para mudar a escala, fazer
translaes e rotaes de estruturas
Labels
Carrega a caixa de dilogo para mudana dos rtulos
das estruturas
Mono/Stereo
Alterna entre a viso mono e estreo
Stick Figure
Mostra todas estruturas como figuras stick (basto)
Ball Stick
Mostra todas estruturas como figuras pau e bola
Pluto
Mostra todas estruturas no modo Pluto de pau e bola
Tubular bonds
Mostra todas estruturas como tubos
CPK Surface
Mostra todas ou as estruturas selecionadas com
superfcie CPK
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Dot Surface
Mostra todas ou as estruturas selecionadas com
superfcie de pontos
Ribbon
Mostra diagrama Ribon para peptdeos ou cidos
nuclicos
Compare
Compara estruturas diferentes
Dihedral Map
Mostra os resultados dos clculos de dihedral drive
Movie
Mostra, em sequncia, as estruturas de um arquivo de
estruturas mltiplas
Menu Analyze
Minimize
Minimiza a estrutura atual
Single point
Calcula a energia da estrutura atual
Mopac
Roda o programa de qumica quntica MOPAC
Ampac
Roda o programa de qumica quntica AMPAC
GMMX
Roda o programa de busca conformacional GMMX
Gaussian
Roda o programa de qumica quntica ab initio
Gaussian
Orbitals
Roda o programa Orbdraw para visualizar os orbitais
moleculares e
as densidades eletrnicas
Vibrations
Roda o programa Vibrator para visualizao dos modos
vibracionais
Dynam
Simulao de dinmica molecular
Dock
Busca das energias de interao mais baixas entre
duas estruturas atravs da
anelao simulada
Batch
L um arquivo de estruturas mltiplo e minimiza todas
estruturas
Rot_E
Avalia a barreira de energia rotacional obtida por rotor
rgido
Dihedral Driver
Avalia a barreira de energia rotacional obtida por busca
seqencial com
minimizao
Surface Area
Calcula a rea da superfcie da molcula
Volume
Calcula o volume da molcula
Menu Substr
Read
L um arquivo de estrutura e rotula a estrutura como
substrutura
Create
Rotula a estrutura selecionada como substrutura
Move
Move a substrutura selecionada
Connect
Liga duas estruturas
Erase
Apaga a substrutura selecionada
Hide
Oculta da tela a substrutura selecionada
Dont Minimize
Marca a substrutura selecionada e esta no ser
minimizada nos clculos de
mecnica molecular
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Menu Mark
H Bonds
Marca as ligaes de hidrognio
Pi atoms
Marca os tomos pi
Metal Coord
Estabelece a soma de eltrons, carga e coordenao
de tomos metlicos
TS_BondOrders Estabelece as ordens de ligao para ligaes de
estados de transio
Fix Atoms
Fixa tomos para no moverem durante a minimizao
Fix Distance
Fixa uma distncia entre quaisquer dois tomos- acima
de 10 pares
Fix Torsions
Fixa ngulos diedro
Resert
Apaga qualquer uma das marcaes acima e tambm
substrutura associada
Menu Options
Printout
Estabelece a quantidade de sada no arquivo de sada,
PCMOD.OUT
Dielc
Apaga a constante dieltrica
DPDP
Troca entre os clculos dipolo-dipolo e os eletrostticos
Minimizer
Estabelece opes para a minimizao
MMX_Pi Calc
Estabelece opes para clculos pi
Standard Constants
Fora o uso do conjunto de dados padro
(default)
Added Constants Permite o uso de constantes adicionais armazenadas
em um arquivo
Stereo
Muda a direo de rotao do mostrador estreo
Pluto
Estabelece opes para a visualizao Pluto
VDW surface
Estabelece opes para a visualizao VDW
Dot surface
Estabelece opes para a visualizao de superfcie de
pontos
Menu Help
About
Verso corrente do PCMODEL
SUMRIO RPIDO DO MENU TOOLS
Select
Seleciona tomos
Draw
Desenha um esqueleto de carbonos ou no plano da tela ou
no plano do primeiro tomo
selecionado
Build
Gera uma estrutura 3-D pela substituio de hidrognios
selecionados por grupos
metila. Iniciando do etano, qualquer hidrognio selecionado ser
substitudo por metila
Update
Atualiza a estrutura e redesenha a tela
H/AD
Adiciona e deleta hidrognios e pares de eltrons livres
Add_B
Aumenta a ordem de ligao da ligao
selecionada
In
Empurra um tomo para dentro do plano da tela
Out
Puxa um tomo para fora do plano da tela
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Del
Deleta um tomo ou ligao
Move
Move um tomo. Selecione Move, selecione o tomo e
selecione a nova posio.
RotB
Roda a ligao central de quatro tomos selecionados
Query
Pergunta distncias, ngulos e diedros selecionados.
Primeiro selecione Query, ento selecione 2, 3 ou 4 tomos seguidos de um
espao branco na janela de desenho. As respostas so removidas pela seleo do
boto Update duas vezes.
PT
Caixa de dilogo para escolher tipos de tomos
Metals
Caixa de dilogo para escolher tipos de metal
Rings
Caixa de dilogo para ler sistemas cclicos selecionados
AA
Caixa de dilogo para ler (e conectar) aminocidos
Su
Caixa de dilogo para ler (e conectar) acares
Nu
Caixa de dilogo para ler nucleosdeos
Cancel
Apaga a caixa de dilogo Tools. A caixa de dilogo pode ser
recuperada usando a opo Draw do menu Edit.
thais@farmacia.ufmg.br
trabalho
em
laboratrios
de
Qumica
Medicinal
requer
documento
foi
supervisionado
pelo
Prof.
Thais
Horta
inexistncia
exerccio
de
(e.g.,
riscos
especficos
toxicidade,
na
realizao
inflamabilidade,
deste
riscos
de
Se
seu
exerccio
ou
prtica
envolver
qualquer
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risco
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EXERCISE III.3
MOLECULAR MODELING WITH THE AID OF A COMPUTER
Thais Horta lvares da Silva
Departamento de Produtos Farmacuticos, Faculdade de Farmcia da Universidade Federal de
Minas Gerais, Belo Horizonte, Minas Gerais 30180-112, Brasil
E-mail: thais@farmacia.ufmg.br
INTRODUCTION
Models are simple representations of real objects and physical phenomena.
Modeling comprises building and manipulation of models with the objective of
acquiring a more thorough comprehension of the represented entities. Molecular
modeling involves the construction, manipulation, and representation of realistic
molecular
structures
and
the
calculation
of
physicochemical
properties.
isomerism
is
defined
as
the
non-identical
spatial
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D
B
Scheme 1
An appropriate system of classification of conformations proposed by Klyne
and Prelog is based on the torsion angle values (Scheme 2 and Table 1).
Table 1 Specification of torsion angle (KlynePrelog).
Designation
Torsion angle,
synperiplanar
30 to +30
+synclinal
30 to +90
+anticlinal
+90 to +150
antiperiplanar
+150 to 150
anticlinal
150 to 90
synclinal
90 to 30
-30
30
SP
-SC
SC
-AC
AC
90
-90
AP
-150
180
150
Scheme 2
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HH
2,8 kcal/ mol
H
H
staggered
HH
eclipsed
CH 3
CH 3
H
H
CH 3
H
CH 3
HH
CH 3
H
H
CH 3
H
CH 3
synperiplanar
H
CH 3
synclinal
anticlinal
antiperiplanar
main
conformations
are
envelope
and
half-chair.
The
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cyclopropane
cyclobutane
cyclopenta
6.9 Kcal/mol
boat cyclohexane
Fig.
5.3 kcal/mol
chair cyclohexane
Conformations
of
cyclopropane,
cyclobutane,
twist-boat cyclohexane
cyclopentane,
and
cyclohexane.
Calculation methods used in molecular modeling can be classic such as
molecular mechanics (MM) or quantic such as ab initio or semi-empirical.
The MM calculations are also known as force field calculations. Molecular
mechanics consider molecules as a collection of atoms that can be described by
Newtonian forces, that is, they are regarded as a collection of particles joined by
harmonic and elastic forces. These forces can be described based on potential
energy functions among other structural characteristics such as bond length, bond
angles, and non-binding interactions. The combination of these functions is the
force field. The total potential energy (Etot) or steric energy of a molecule can be
simply represented by Westheimers equation:
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ETot = Es + Eb + Ew + Enb + EE
Es - energy of bond deformation (stretching or compression of a bond),
Eb - energy of bending (angular deformation),
Ew - torsional energy (w is the bond torsional angle),
Enb - energy of non-bonding interactions, and
EE - electrostatic energy.
2
l
(
)
K
l
l
0
E=
2
l
K (
Eb =
K - angle bending force constant
- actual angle
0 - unstrained angle
=
w
)2
Vw
(1 cos nw)
2
E nb = Fr 6 + exp[12(1 )]
Fr - force constant
=
r____
r 1* + r 2*
r - nonbonded atoms distance
r1* and r2* - van der Waals distances
Eelect= Q1Q2/ r
Q1 and Q2 - atomic charges
- dielectric constant
r - interatomic distance
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useful.
More
detailed
structure
information
emerges
from
X-ray
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Nevertheless, the preferable conformations in gas and solid state are not
necessarily the same as in solution.
Ab initio and semi-empirical quantum-mechanical methods are based on a
set of laws known as quantum mechanics. The application of quantum mechanics
to chemical problems is known as quantum chemistry. To describe the state of a
system in quantum mechanics, the existence of a function of coordinates called
wave function, or state function , was postulated, that is the solution of
Schrdingers equation (Fig. 5). The wave function contains all possible information
about the system that it describes and, from it, we can calculate all the electronic
properties of the molecule.
H = E
Fig. 5 Schrdingers equation.
Ab initio quantum-mechanical methods are that where Schrdingers
equation is solved with more approximation. At the semi-empirical quantummechanical methods, some integrals used to solve Schrdingers equation are
substituted by empirical parameters that fit as closely as possible to experimental
data. The semi-empirical methods were created in order to reduce the high cost of
computer time. They are applied to medium molecular systems.
This chapter describes the conformational analyses of acetylcholine and
muscarine using the systematic search method, and the superimposition of their
preferred conformations using the PCMODEL 7.0 software. As a supplemental
exercise, we also have students match these conformations with the proposed
structure of the muscarinic acetylcholine receptor.
The force field used in PCMODEL is called MMX, and it is derived from the
MM2 force field of N. L. Allinger. The current version of MMX recognizes nearly
60 different atom types including radicals, anions, cations, transition metals,
and transition-state atoms, some of which are not handled in MM2.
There are several ways of accessing a chemical structure on the computer.
Drawing it on the screen using the program drawing tools and the libraries
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available (PCMODEL displays ring, amino acid, sugar, and nucleotide libraries),
reading a file saved in another program that the actual program reads
(PCMODEL opens MMX, MM3, PDB, MOPAC, ALCHEMY, SYBYL, X-RAY,
MDL_MOL,
MACROMODEL,
GAUSSIAN,
JAGUAR,
CAMBRIDGE
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O
2
1
O
0 1 2
3
N+
6
10
PROCEDURES
The PCMODEL screen is a 2D plane. The first point to be drawn is the 0 of Z-axis,
and the screen is the XY plane. Use in and out tools to move atoms back and forth
along Z-axis and just left-click with the mouse cursor to select a menu option. The
right mouse button rotates the molecule, and it is always activated. The molecule
rotates along the y-axis by right-click-dragging the mouse left and right in the
workspace. It rotates along the x-axis by right-click-dragging up and down.
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This command calls up the PERIODIC TABLE dialog box. Choose oxygen and
left-click on C3 and C8. After that, choose N+ (positive nitrogen) and left-click on
C6.
(9) Adding hydrogens and non-bonding electron pairs. Click on H/AD on the
TOOLS menu.
(10) Optimizing the isolated molecule (energy minimization). Select MMX force
field on the FORCE FIELD menu and MINIMIZE on the ANALYSE menu. The
OUTPUT dialog box opens.
It shows information about steric energy (Kcal/mol), heat of formation
(Kcal/mol) and dipole moment.
(11) Saving the structure. Select SAVE on the FILE menu. The SAVE AS dialog
box opens. Select the folder where you want to save the file, write its name and
select the format. Available formats: PCMODEL format (PCM), MMX, MM3,
MOPAC, ALCHEMY, SYBYL, MACROMODEL, CHEM-3D, PDB, JAGUAR,
GAUSSIAN e GAMES. Finally, select SAVE.
(12)
molecule rotates).
Select PLUTO on the VIEW menu.
Select TUBULAR BONDS on the VIEW menu.
Select CPK on the VIEW menu.
Select DOT SURFACE on the VIEW menu.
(13) Exiting. Select EXIT on the FILE menu.
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180 due to the partial double bond of the C2-O3 bond. The angles 1, 2, and 3 are
180 and correspond to a distended chain. This is the initial and standard
conformation for all students to start their conformational analysis.
(1) Open PCMODEL.
(2) Open acetylcholine file by choosing OPEN on the FILE menu.
(3) Choose SEL-ATM on the TOOLS menu and mark C1, C2, O3 and C4 (0).
Select ROT-B option on the TOOLS menu. A dialog box will appear displaying the
current value in degrees of 0. Drag the scroll box until a value next to 180 or
180. Repeat the procedure for 1, 2, and 3.
(4) Choose SEL-ATM on the TOOLS menu and mark O3, C4, C5 e N6 (2).
(5) Select DIHEDRAL DRIVER on the ANALYSE menu. A dialog box will appear
displaying the current dihedral angle value. The required values must be entered.
Start angle: X (X is an integer number multiple of 5 and nearest the
initial angle).
Final angle: X + 350 (to complete a 360 rotation along C4-C5 bond).
Step: 10.
And select OK.
(6) A new dialog box will appear for entering the filename for the output structures.
This is a multiple structure file where the coordinates for each step are saved (for
instance, ACHDDxx.PCM). The filename must be different from the structure
name. Click on SAVE to begin the calculation.
(7) In the end, a window with a graphical result (DIHEDRAL MAP) will appear. This
contour map represents the surface of potential energy (SEP) that relates steric
energy with 2 angle. These calculations produce 36 conformations of different
energy.
(8) Select PRINT on the file menu.
(9) Find minimum energy points in the SEP, and fill in Table 2 with the values of 2
and steric energy (SE).
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Conformation
SE (kcal/mol)
A
B
C
(10) Find maximum energy points in the SEP and fill in Table 3.
(11) Classify the conformations as synperiplanar (SP), synclinal (SC), anticlinal
(AC), or antiperiplanar (AP) and include this information on Tables 2 and 3.
Table 3 Maximum energy conformations of Ach.
Conformatio
SE (kcal/mol)
N6)
1
2
3
SE
#dihd 0
6,848
#dihd 1
6,878
X+10
#dihd 2
8,548
X+20
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#dihd 3
X+30
#dihd 35
X+350
(d) Select the desired conformation (conformations A, B, and C, Table 2) and click
on OK. The selected conformation appears on the workspace (to find minimum
conformations, just compare minimum SE values of each conformation, it will be a
minimum if the value is smaller than the previous and the next conformations).
(e) De-select dihedral driver atoms by choosing RESET on the MARK menu.
(f) Optimize the structure by choosing MINIMIZE on the ANALYSE menu.
(2) Select QUERY on the TOOLS menu and select 2, 3, or 4 atoms (2 atoms to
measure distances, 3 atoms to measure angles and 4 atoms for dihedral angles)
and any point on the workspace. The measures appear on the screen.
(3) Fill in Table 4 for each minimum conformation of acetylcholine.
Table 4 Acetylcholine minimum energy conformations after minimization.
Conformation
#dihd
O3-N6 (A)
C1-N6(A)
N6-O8(A)
A
B
C
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SE
2 =
2 =
A
2 =
SUPPLEMENTARY EXERCISES
*N
*
H3C
CH3
*
*
O
*
*
CH3
*
O
*
O
*O
O*
CH3
*N(CH3)3 O
nicotine
*
* N+(CH3)3
O
CH3
*O
*
*
*
+
*N(CH3)3
pilocarpine
CH3
*
H
*N+(CH3)3
After that, perform the geometry optimization and write down the energies.
4) Draw Newman projection for the structures above using the marked atoms (*)
to form a dihedral angle.
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Scheme 3
CONCLUSION
REFERENCES
FRHBEIS, H.; KLEIN, R.; WALLMEIER, H. Angew. Chem. Int. Ed. Engl., v. 26, p.
403-418, 1987.
BECKETT, A.H.; HARPER, N.J.; LESSER, E.; CLINTHEROW, J.W. Nature 1961,
189, 671-673.
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Hide Hydrogens
Epimer
Enantiomer
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Copy_To_Clipboard
Orient_XY
Orient_XZ
Menu View
Control Panel
Labels
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Compare
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Minimize
Single Point
Mopac
Ampac
GMMX
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Vibrations
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Dock
Batch
Rot_E
Dihedral Driver
Surface Area
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Volume
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About
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Set electron count, charge, and coordination of
metal atoms
Set the bond orders for transition-state bonds
Fix atoms to not move during minimization
Fix a distance between any two atomsup to 10
pairs
Fix dihedral angle
Reset any above and also substructure
membership
Set the amount of output in the output file
Reset the dielectric constant
Change between dipole-dipole and electrostatic
calculations
Set options to minimize
Set options to pi calculations
Force the use of default data set
Allow the use of additional constants stored in a
file
Change the direction of rotation of stereo display
Set options to Pluto
Set options to VDW
Set options to dot surface
Current version of PCMODEL
Select atoms
Draw a carbon skeleton in either the plane of the
screen or the plane of the first selected atom
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Build
Update
H/AD
Add_B
In
Out
Del
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RotB
Query
PT
Metals
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AA
Su
Nu
Cancel
handling
of
electrical
instruments,
heating
elements,
This
document
has
been
supervised
by
Prof.
Thais
Horta
no
special
risk
(regarding
toxicity,
inflammability,
Chemistry
laboratory
exist
when
performing
exercise.
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this
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