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Molecular Modelling Portfolio 2009
Information on ligand
CHEMICAL NAME
6-BENZO[1,3]DIOXOL-5-YL-2-METHYL-2,3,6,7,12,12A-HEXAHYDRO-PYRAZINO[1',2':1,6]PYRIDO[3,4-B]INDOLE-1,4-DIONE
COMMON NAME TADALAFIL, CIALIS
MOLECULAR FORMULA C22 H19 N3 O4
SMILES STRINGCN1CC(=O)N2[CH](Cc3c([nH]c4ccccc34)[CH]2c5ccc6OCOc6c5)C1=O
2D structure of ligand :
Fig 1: Tadalafil (2D structure)
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Molecular Modelling Portfolio 2009
3D structure of ligand :
Fig 2: Tadalafil (3D structure)
Ligand optimization by MOPAC
Information as in Table 2 is obtained by ligand poptimization, after running mopac process in VEGA. The structure of the ligand after energy minimization changes to as in Fig 3.
Parameters Values
HEAT OF FORMATION -17.929575 KCAL
ELECTRONIC ENERGY -39795.618392 EV
CORE-CORE REPULSION 34817.754630 EV
GRADIENT NORM 20.380683
DIPOLE 1.53840 DEBYE
NO. OF FILLED LEVELS 73
IONIZATION POTENTIAL 8.477715 EV
MOLECULAR WEIGHT 389.410
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Molecular Modelling Portfolio 2009
SCF CALCULATIONS 116
COMPUTATION TIME 14.984 SECONDS
Table 2
Fig 3: ligand structure after energy minimization
Chiral Centres: On detecting stereo chemistry of ligand in Chem Bio3D software, Two chiral carbon atoms were found to be
present at C11(S) and C13(R).
Molecular Propertis: Following details were obtained by computing properties of ligand Chem Bio 3D software. Various properties of
ligand is given in Table 1.
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Molecular Properties Values
LogP 1.128
Mol Refractivity 10.610
Mol Weight 389.40396
Partition Coefficient 2.583999
Polar Surface Area 71.11Angstrom Squared
Number of Rotatable Bonds 1bond
Henry's Law Constant 20.972
Molecular Modelling Portfolio 2009
Table- 1
Information on Protein
The PDB code given to me was 1UDU. I inserted that code in PDB site and reached to my protein, which was Human Phosphodiesterase 5 enzyme. IT is form the phosphopdiesterase class of proteins. This enzyme can be found mainly in corpus cavernosum and retina, but it is also present in some of the other tissues such as platelets, smooth muscles and skeletal muscles in lower concentrations. PDE5 is target for many diseases such as heart failure, depression, asthma, inflammation and erectile dysfunctions. PDE5 has ability to degrade intracellular second messenger cAMP and cGMP. In corpus cavernosum tissue PDE5 hydrolyses the cGMP, hence it is a suitable drug target for sidenafil and tadalafil(Viagra) like drugs. Sidenafil and tadalafil bind to the PDE5 catalytic site with high affinity and specificity. These drugs are used to treat erectile dysfunction.
Sequence for Phosphodiesterase chain A
1 TRELQSLAAA VVPSAQTLKI TDFSFSDFEL SDLETALCTI RMFTDLNLVQ TTHHHHHSS TTTTTT T TT STTS HHHHHHHHH HHHHTTTHHH
51 NFQMKHEVLC RWILSVKKNY RKNVAYHNWR HAFNTAQCMF AALKAGKIQN HTT HHHHH HHHHHHHHTS TTSSSSSHH HHHHHHHHHH HHHTTTT GG
101 KLTDLEILAL LIAALSHDLD HRGVNNSYIQ RSEHPLAQLY CHSIMEHHHF GS SHHHHHH HHHHTSTTTT S SHHHHHHH
151 DQCLMILNSP GNQILSGLSI EEYKTTLKII KQAILATDLA LYIKRRGEFF HHHHHHHHST T TTTTS H HHHHHHHHHH HHHHTT HH HHHSSTTTTT
201 ELIRKNQFNL EDPHQKELFL AMLMTACDLS AITKPWPIQQ RIAELVATEF TTTTT S SSHHHHHHHH HHHHHHHHGG GGGS HHHHH HHHHHHHHHH
251 FDQGDRERKE LNIEPTDLMN REKKNKIPSM QVGFIDAICL
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Molecular Modelling Portfolio 2009
QLYEALTHVS HHHHHHTTTS S STTS SS TTSHHHH HHHHHHHTHH HHHHHHHHH
301 EDCFPLLDGC RKNRQKWQAL AEQQ GGGHHHHHHH HHHTTTHHHH HTT
Table2
Cavities without Ligand:
Q-site finder is a software, which can predict the possible binding sites of ligand in protein molecule. Fig 3 obtained from this software shows almost 10 possible binding sites for tadalafil ligand molecule in protein structure. These binding sites are in different colours as shown in Fig 3.
Fig 3: ligand binding sites
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Molecular Modelling Portfolio 2009
Missing Residues:
PDB file can be open in chimera by clicking on Fetch by PDB ID.
Moreover it can be saved in PDB in format in chimera. by doing so, that saved file can
also be opened in notepad, which gives complete details about protein structure such as
name if residues, in what chain they are present, sequence number of residues, name of
the ligand present in it, class of the protein and also missing residues. From the obtained
details I have selected information about missing residues of protein which is presented in
Table 3
Residue Name Chain Sequence Number
ILE A 665
GLN A 666
ARG A 667
SER A 668
GLU A 669
HIS A 670
PRO A 671
LEU A 672
ALA A 673
GLN A 674
LEU A 675
ILE B 665
GLN B 666
ARG B 667
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Molecular Modelling Portfolio 2009
SER B 668
GLU B 669
HIS B 670
PRO B 671
LEU B 672
ALA B 673
GLN B 674
LEU B 675
Table 3
Is it a part of bigger protein?
In chimera software, “higher-order structure” is available in tool bar. By clicking on it, we can reach to the ‘make unit cell option’. That option shows all other supporting molecules of the protein. However, all other protein molecules are exactly same in all manners as shown in Fig 4. From this information it is understood that the given phosphodiesterase enzyme molecule is actually a part of bigger protein.
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Molecular Modelling Portfolio 2009
Fig 4: Complete protein molecule (unit cell)
Secondary Structure Composition
Chimera is useful tool in determining secondary structure composition of protein. Secondary structure of the given protein was found to be as in Fig 5 for my protein.
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Molecular Modelling Portfolio 2009
Fig 5 Secondary Structure
LIGPLOT
Fig 6 Ligplot
INTERACATIONS
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Molecular Modelling Portfolio 2009
Atom 1 Atom 2 Distance Type
A:1003:CIA:C2 A:612:TYR:CE1 3.60 Hydrophobic
A:1003:CIA:C2 A:612:TYR:CZ 3.41 Hydrophobic
A:1003:CIA:C1 A:782:VAL:CG2 3.59 Hydrophobic
A:1003:CIA:C7 A:820:PHE:CE2 3.80 Hydrophobic
A:1003:CIA:C8 A:820:PHE:CD2 3.67 Hydrophobic
A:1003:CIA:C8 A:820:PHE:CE2 3.71 Hydrophobic
A:1003:CIA:N9 A:817:GLN:OE1 2.55 Hydrogen Bond
A:1003:CIA:C13 A:820:PHE:CG 3.83 Hydrophobic
A:1003:CIA:C13 A:820:PHE:CD2 3.74 Hydrophobic
A:1003:CIA:C17 A:804:LEU:CD1 3.69 Hydrophobic
A:1003:CIA:O20 A:816:MET:O 2.85 Hydrogen Bond
A:1003:CIA:C16 A:804:LEU:CD2 3.75 Hydrophobic
A:1003:CIA:C11 A:820:PHE:CD1 3.66 Hydrophobic
A:1003:CIA:C11 A:820:PHE:CE1 3.45 Hydrophobic
A:1003:CIA:C11 A:820:PHE:CZ 3.63 Hydrophobic
A:1003:CIA:C10 A:786:PHE:CZ 3.83 Hydrophobic
A:1003:CIA:C18 A:663:SER:CA 3.10 Hydrophobic
A:1003:CIA:C18 A:663:SER:C 3.48 Hydrophobic
A:1003:CIA:C22 A:804:LEU:CD1 3.72 Hydrophobic
A:1003:CIA:C27 A:804:LEU:CD1 3.55 Hydrophobic
A:1003:CIA:C27 A:816:MET:C 3.40 Hydrophobic
A:1003:CIA:C27 A:816:MET:CB 3.57 Hydrophobic
A:1003:CIA:C27 A:817:GLN:CA 3.84 Hydrophobic
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Molecular Modelling Portfolio 2009
A:1003:CIA:C27 A:817:GLN:CG 3.80 Hydrophobic
A:1003:CIA:C27 A:817:GLN:CD 3.82 Hydrophobic
A:1003:CIA:C26 A:804:LEU:CD1 3.54 Hydrophobic
A:1003:CIA:C26 A:816:MET:CB 3.29 Hydrophobic
A:1003:CIA:C25 A:804:LEU:CD1 3.69 Hydrophobic
A:1003:CIA:C29 A:783:ALA:CA 3.31 Hydrophobic
A:1003:CIA:C29 A:783:ALA:CB 3.52 Hydrophobic
A:1003:CIA:C29 A:787:PHE:CE1 3.50 Hydrophobic
A:1003:CIA:C24 A:786:PHE:CD1 3.75 Hydrophobic
A:1003:CIA:C24 A:804:LEU:CD1 3.85 Hydrophobic
A:1003:CIA:C23 A:782:VAL:CG1 3.78 Hydrophobic
A:1003:CIA:C23 A:786:PHE:CD1 3.88 Hydrophobic
A:1003:CIA:C23 A:786:PHE:CE1 3.82 Hydrophobic
A:1003:CIA:C23 A:804:LEU:CD1 3.86 Hydrophobic
Table 4
From the ligplot Fig 5 and Table 4 about interactions of ligand with the receptor, it is very well clear that ligand binds with the receptor with high affinity and specificity. Most of the ligand-protein interactions are hydrophobic in nature; however two hydrogen bonds are also present, hydrogen of pyrole nitrogen atom and oxygen of carbonyl group of 817 amino acid forms a hydrogen bond. Whereas, another hydrogen bond is formed between oxygen atom of carbonyl group of 816 amino acid and hydrogen atom dioxolane ring. Length of these two hydrogen bonds are 2.55A N and 2.85A N respectively.
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Molecular Modelling Portfolio 2009
Protein-ligand complex
Two molecules of ligand (tadalafil) bind in protein at two different positions. Ligand binding in the structure can be illustrated in three different ways as in Fig 7a, 7b and 7c. According to me Fig 7a represents the ligand binding with protein in most proper way.
Fig 7a
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Molecular Modelling Portfolio 2009
Fig 7b
Fig 7c
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