In silico technique was applied to screen potential of 16 compounds of 5,5-dimethylthiohydantoin derivatives as androgen antagonist. The 3D structure of the protein was obtained from PDB database. Docking analysis of the compounds was performed using hex docking. Molecular modeling analysis exhibits relatively low LUMO-HOMO energy gap of the studied molecules, indicating that it would be kinetically stable. None of the compounds violated Lipinski’s parameters, making them potentially promising agents for biological activities. The title compounds exhibited the lowest docking energy of protein-ligand complex. Finally, the results indicate that these compounds are potentially as an androgen antagonist, and expected to be effective in prostate cancer treatment.
Cancer can be characterized by the arrest of cell differentiation, the inhibition of apoptosis and the accelerated proliferation of cloned cells. The understanding of the mechanisms of cell-death execution and the role that they play in different diseases opens new therapeutic strategies [
However, the AR is a cytoplasmic protein and is a member of the steroid/thyroid hormone receptor superfamily [
AR antagonists are used as a single agent (monotherapy) or in combination with castration. The latter use, referred to as “combined androgen blockade therapy”, shows significant effects by blocking adrenal androgen signals as well as suppressing the transient testosterone increase induced by GnRH analogs [
Although, the antiandrogens exhibit good efficacy in many cases and comprise an important part of effective therapeutics [
The thiohydantoin derivative with a carboxyl terminal side chain showed that pure antagonistic activities in vitro and oral AR antagonistic activity in vivo [
The available data sets of 16 compounds were obtained from the literature [
All the calculations are performed by using Gauss view 5.0 molecular visualization program and Gaussian 09 program package on the personal computer [
Computation of molecular descriptors such as partition coefficient, topological surface area and a number of hydrogen bond acceptors & donors, was carried out using Mol inspiration online tool [
Compound No. | R | IUPAC name |
1 | (CH2)3CONH2 | 4-[3-(4-Cyano-3-trifluoromethylphenyl)-5,5-dimethyl-4- oxo-2-thioxoimidazolidin-1-yl]butyramide |
2 | (CH2)3 NH2 | 4-[3-(3-Aminopropyl)-4,4-dimethyl-5-oxo-2- thioxoimidazolidin-1-yl]-2-trifluoromethylbenzonitrile |
3 | (CH2)3 NH CO NH2 | 3-[3-(4-Cyano-3-trifluoromethylphenyl)-5,5-dimethyl-4- oxo-2-thioxoimidazolidin-1-yl]propylurea |
4 | (CH2)3 NHSO2NH2 | N-(3-{3-[4-cyano-3-(trifluoromethyl) phenyl]-5,5-dimethyl-4- oxo-2-sulfanylideneimidazolidin-1-yl}propyl) aminosulfonamide |
5 | (CH2)3 SO3H | 3-[3-(4-Cyano-3-trifluoromethylphenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1-yl] propane-1-sulfonic acid |
6 | (CH2)3 SO2 NH2 | 3-[3-(4-Cyano-3-trifluoromethylphenyl)-5,5-dimethyl-4- oxo-2-thioxoimidazolidin-1-yl]propane-1-sulfonamide |
7 | (CH2)4 SO2NH2 | 4-[3-(4-Cyano-3-trifluoromethylphenyl)-5,5-dimethyl-4- oxo-2-thioxoimidazolidin-1-yl]butane-1-sulfonamide |
8 | (CH2)2 SO2NH2 | 2-[3-(4-Cyano-3-trifluoromethylphenyl)-5,5-dimethyl-4- oxo-2-thioxoimidazolidin-1-yl] ethanesulfonamide |
9 | (CH2)2 SO2NHMe | 3-[3-(4-Cyano-3-trifluoromethylphenyl)-5,5-dimethyl-4- oxo-2-thioxoimidazolidin-1-yl] propane-1-sulfonic acid methylamide |
10 | (CH2)2 SO2NHMe2 | 3-[3-(4-Cyano-3-trifluoromethylphenyl)-5,5-dimethyl-4- oxo-2-thioxoimidazolidin-1-yl] propane-1-sulfonic acid dimethylamide |
Compound No. | R1, R2 and R3 | IUPAC NAME |
11 | R1 = R2 = R3 = H | 3-[3-(4-Cyanophenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1-yl]propane-1-sulfonamide |
12 | R1 = Me, R2 = R3 = H | 3-[3-(4-Cyano-3-methylphenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1-yl]propane-1-sulfonamide |
13 | R1 = OMe, R2 = R3 = H | 3-[3-(4-Cyano-3-methoxyphenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1-yl]propane-1-sulfonamide |
14 | R1 = Cl, R2 = R3 = H | 3-[3-(3-Chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2- thioxoimidazolidin-1-yl]propane-1-sulfonamide |
15 | R1 = CF3, R2 = Me, R3 = H | 3-[3-(4-Cyano-2-methyl-3-trifluoromethylphenyl)-5,5- dimethyl-4-oxo-2-thioxoimidazolidin-1-yl]propane-1- sulfonamide |
16 | R1 = CF3, R2 = H, R3 = Me | 3-[3-(4-Cyano-2-methyl-5-trifluoromethylphenyl)-5,5- dimethyl-4-oxo-2-thioxoimidazolidin-1-yl]propane-1- sulfonamide |
In the present study, Bioinformatics tools are used, biological databases like PDB (Protein Data Bank) and the software’s like Hex [
The activity prediction of all molecules has been achieved by PASS server and compared with hydroxyflutamide. PASS Online predicts over 3500 kinds of biological activity, including pharmacological effects, mechanisms of action, toxic and adverse effects, interaction with metabolic enzymes and transporters, influence on gene expression, etc. Prediction is based on the analysis of structure activity-relationships for more than 250,000 biologically active substances including drugs, drug-candidates, leads and toxic compounds. The structural formula only is necessary to obtain the predicted biological activity profile for any compound.
Hex is an interactive molecular graphics program for calculating and displaying feasible docking modes of pairs of protein and DNA molecules. Hex can also calculate protein-ligand docking; assuming the ligand is rigid, and it can superpose pairs of molecules using only knowledge of their 3D shapes [
The docking analysis of hydroxyflutamide with androgen receptor was carried by HEX docking software. Docking allows the scientist to virtually screen a database of compounds and predict the strongest binders based on various scoring functions. It explores ways in which two molecules, such as drugs and an enzyme; Human estrogen receptor fit together and docks to each other well, like pieces of a three-dimensional jigsaw puzzle. The molecules binding to a receptor, inhibit its function, and thus act as a drug.
The parameters used in the docking process were
・ Correlation type―Shape only
・ FFT Mode―3D fast lite
・ Grid Dimension―0.6
・ Receptor range―180
・ Ligand Range―180
・ Twist range―360
・ Distance Range―40
All water molecules and ligands were removed from the proteins for docking studies.
The hydroxyflutamide and 5,5-dimethylthiohydantoin derivatives were docked with the receptor using the above parameters. Visualization of the docked pose had been done using a PyMol molecular graphics program [
Two-dimensional representations of the best docking pose for selected 5,5-dimethylthiohydantoin derivatives inside target enzyme were generated using LigPlot+ [
Binding sites and active sites of proteins and DNAs are often associated with structural pockets and cavities. CASTp server uses the weighted Delaunay triangulation and the alpha complex for shape measurements. It provides identification and measurements of surface accessible pockets as well as interior inaccessible cavities, for proteins and other molecules. It measures analytically the area and volume of each pocket and cavity, both in the solvent accessible surface (SA, Richards’ surface) and molecular surface (MS, Connolly’s surface). It also measures the number of the mouth openings, area of the openings, and circumference of mouth, lips, in both SA and MS surfaces for each pocket [
The ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) properties of the target compounds were calculated using some web-based applications. BBB (Blood-Brain Barrier) penetration, HIA (Human Intestinal Absorption), Caco-2 cell permeability and Ames test were calculated using admetSAR [
The frontier molecular orbitals for all compounds have been presented in Figures 2(a)-(d). The molecular orbital shows that, the location of possible sites responsible for electron transfer between molecules and its biological target. Thus, we can discover that how molecules react and where is the active sites in reaction. For the molecules 1-10, the HOMO are delocalized on thiohydantoin system and part of the benzene ring, while in the LUMO, the electron density predominantly are located on the benzene ring, C≡N group, thiohydantoin system except N atom which linked to benzene ring and C=O group. On the other hand, in the case of the molecules 11 and 12, the HOMO are delocalized on thiohydantoin system and part of the benzene ring, while in the LUMO, the electron density predominantly are located on the benzene ring, C≡N group, thiohydantoin system and CH2-SO2-NH2 system. However, in the case of the molecule 13, the HOMO are delocalized on thiohydantoin system, the benzene ring and O atom linked to phenyl ring, while in the LUMO, the electron density predominantly are located on the benzene ring, C≡N group, thiohydantoin system and CH2-SO2-NH2 system. In the case of molecule 14, the HOMO are delocalized on thiohydantoin system, Cl atom and part of the benzene ring, while in the LUMO, the electron density predominantly are located on the benzene ring, C≡N group, thiohydantoin system, Cl atom and SO2 system. But, the HOMO of molecule 15 are delocalized on thiohydantoin system, while in the LUMO, the electron density predominantly located are on the benzene ring, C≡N group and thiohydantoin system. However, the HOMO of molecule 16 are delocalized on thiohydantoin system, while in the LUMO, the electron density predominantly are located on the benzene ring, C≡N group and part of
thiohydantoin system.
The energies of the frontier orbital (EHOMO and ELUMO) obtained with the AM1 semiempirical method are presented in
In the framework of density functional theory (DFT) global descriptors of chemical reactivity corresponds to global responses of systems to global perturbations (for instance, changes in the number of electrons N), whereas the external potential remains constant. Among such types of indexes, chemical potential (μ), chemical hardness (η) and softness (s) can be used as complementary tools in the description of thermodynamic aspects of chemical reactivity.
From equation (1), the first order partial derivatives of total energy (E) with respect to the number of electrons
Compound No. | Lumo | Homo | Lumo-Homo | Hardness | Hf kcal/mol |
---|---|---|---|---|---|
1 | −0.04604 | −0.34227 | 0.29623 | 0.148115 | −134.037 |
2 | −0.04247 | −0.33717 | 0.29470 | 0.147350 | −90.6825 |
3 | −0.04198 | −0.33679 | 0.29481 | 0.147405 | −125.751 |
4 | −0.04377 | −0.33874 | 0.29497 | 0.147485 | −163.745 |
5 | −0.04559 | −0.34209 | 0.29650 | 0.148250 | −208.489 |
6 | −0.04221 | −0.33773 | 0.29552 | 0.147760 | −159.117 |
7 | −0.04333 | −0.33785 | 0.29452 | 0.147260 | −166.572 |
8 | −0.04819 | −0.34521 | 0.29702 | 0.148510 | −153.122 |
9 | −0.04217 | −0.33766 | 0.29549 | 0.147745 | −155.617 |
10 | −0.04205 | −0.33745 | 0.29540 | 0.147700 | −150.352 |
11 | −0.03027 | −0.32958 | 0.29931 | 0.149655 | −8.83272 |
12 | −0.02941 | −0.32823 | 0.29882 | 0.149410 | −15.6560 |
13 | −0.02938 | −0.32712 | 0.29774 | 0.148870 | −42.8924 |
14 | −0.03430 | −0.33500 | 0.30070 | 0.150350 | −13.4327 |
15 | −0.04058 | −0.33698 | 0.29640 | 0.148200 | −160.789 |
16 | −0.04315 | −0.34082 | 0.29767 | 0.148835 | −167.172 |
(N) at constant external potential,
Operational schemes for the calculation of chemical hardness are based on a finite difference method and thus,
where, I・P = Ionization Potential and E・A = Electron Affinity. Using the Koopmans’ theorem in terms of the energies of highest occupied molecular orbital (EHOMO) and lowest unoccupied molecular orbital (ELUMO), according equation (5) & (6) as follow
So that, the equation 3 & 4 can be expressed as follows.
Electron affinity refers to the capability of the ligand to accept precisely one electron from a donor. However, in many kinds of bonding viz. covalent hydrogen bonding, partial charge transfer takes places. Softness (S) is a property of the compound that measures the extent of chemical reactivity. It is the reciprocal of hardness.
Recently Parr et al. [
This index measures the stabilization in energy when the system acquired an additional electronic charge from the environment. Electrophilicity encompasses both the abilities of an electrophile to acquire an additional electronic charge and the resistance of the system to exchange electronic charge with the environment. It contains information about both electron transfer (chemical potential) and stability (hardness) and is a better descriptor of global chemical reactivity. On the other hand, electron affinity (EA) ionization potential (IP), molecular softness, electrophilic index and electronegativity (X) were derived from these results of HOMO and LUMO as per
A computational study for prediction of ADME properties of all molecules is presented in
Compound No. | Electron affinity (EA) | Ionization potential(IP) | Molecular softness | Electrophilic index | Electronegativity X |
---|---|---|---|---|---|
1 | 0.04604 | 0.34227 | 6.751510651 | 0.127253026 | −0.1941550 |
2 | 0.04247 | 0.33717 | 6.786562606 | 0.122265465 | −0.1898200 |
3 | 0.04198 | 0.33679 | 6.784030392 | 0.121660318 | −0.1893850 |
4 | 0.04377 | 0.33874 | 6.780350544 | 0.124007442 | −0.1912550 |
5 | 0.04559 | 0.34209 | 6.745362563 | 0.126724943 | −0.1938400 |
6 | 0.04221 | 0.33773 | 6.767731456 | 0.122118980 | −0.1899700 |
7 | 0.04333 | 0.33785 | 6.790710308 | 0.123334742 | −0.1905900 |
8 | 0.04819 | 0.34521 | 6.733553296 | 0.130263585 | −0.1967000 |
9 | 0.04217 | 0.33766 | 6.768418559 | 0.122060669 | −0.1899150 |
10 | 0.04205 | 0.33745 | 6.770480704 | 0.121885790 | −0.1897500 |
11 | 0.03027 | 0.32958 | 6.682035348 | 0.108158784 | −0.1799250 |
12 | 0.02941 | 0.32823 | 6.692992437 | 0.107009546 | −0.1788200 |
13 | 0.02938 | 0.32712 | 6.717270101 | 0.106714121 | −0.1782500 |
14 | 0.03430 | 0.33500 | 6.651147323 | 0.113387504 | −0.1846500 |
15 | 0.04058 | 0.33698 | 6.747638327 | 0.120235791 | −0.1887800 |
16 | 0.043735 | 0.33855 | 6.783915337 | 0.123926718 | −0.1911425 |
Compound no. | Logp | TPSA A2 | (% ABS) | MW | HBA | HBD | N vio | Nrotb | Volume A3 | |
---|---|---|---|---|---|---|---|---|---|---|
≤5 | - | - | ˂500 | ˂10 | ˂5 | ≤1 | - | - | ||
1 | 2.319 | 90.4330 | 77.80062 | 398.410 | 6 | 2 | 0 | 6 | 324.075 | |
2 | 2.121 | 73.3620 | 83.69011 | 370.400 | 5 | 2 | 0 | 5 | 305.091 | |
3 | 2.378 | 102.460 | 73.65130 | 413.425 | 7 | 3 | 0 | 6 | 336.477 | |
4 | 1.862 | 119.531 | 67.76181 | 449.480 | 8 | 3 | 0 | 7 | 348.925 | |
5 | 0.400 | 101.709 | 73.91040 | 435.449 | 7 | 1 | 0 | 6 | 333.252 | |
6 | 2.102 | 107.504 | 71.91112 | 434.465 | 7 | 2 | 0 | 6 | 336.523 | |
7 | 0.671 | 101.709 | 73.91040 | 449.476 | 7 | 1 | 0 | 7 | 350.054 | |
8 | 1.832 | 107.504 | 71.91112 | 420.438 | 7 | 2 | 0 | 5 | 319.721 | |
9 | 2.477 | 93.5080 | 76.73974 | 448.492 | 7 | 1 | 0 | 7 | 354.197 | |
10 | 2.722 | 84.7190 | 79.77195 | 462.519 | 7 | 0 | 0 | 7 | 371.140 | |
11 | 1.279 | 107.504 | 71.91112 | 366.468 | 7 | 2 | 0 | 5 | 305.225 | |
12 | 1.656 | 107.504 | 71.91112 | 380.495 | 7 | 2 | 0 | 5 | 321.786 | |
13 | 1.264 | 116.738 | 68.72539 | 396.494 | 8 | 2 | 0 | 6 | 330.771 | |
14 | 1.885 | 107.504 | 71.91112 | 400.913 | 7 | 2 | 0 | 5 | 318.761 | |
15 | 2.479 | 107.504 | 71.91112 | 448.492 | 7 | 2 | 0 | 6 | 353.083 | |
16 | 2.479 | 107.504 | 71.91112 | 448.492 | 7 | 2 | 0 | 6 | 353.083 | |
HOF | 2.076 | 95.1500 | 76.17325 | 292.213 | 6 | 2 | 0 | 4 | 227.700 | |
LogP, logarithm of compound partition coefficient between n-octanol and water; TPSA, topological polar surface area; % ABS, percentage of absorption; MW, molecular weight HBA, number of hydrogen bond acceptors; HBD, number of hydrogen bond donors; Nrotb, number of rotatable bonds; Nvio, Number of violations.
good membrane permeability have logP ≤ 5, molecular weight ≤ 500, a number of hydrogen bond acceptors ≤ 10, and a number of hydrogen bond donors ≤ 5. This rule is widely used as a filter for drug-like properties. Furthermore, none of the compounds violated Lipinski’s parameters, making them potentially promising agents for biological activities. On the other hand, the number of rotatable bonds is important for conformational changes of molecules under study and ultimately for the binding with receptors or channels. It is revealed that for passing oral bioavailability criteria, a number of rotatable bonds should be ≤10 [
% ABS = 109 ? (0.345 × TPSA) as reported [
The activity of all test compounds and the standard drug (Flutamide) were rigorously analyzed under four criteria of known successful drug activity in areas of GPCR ligand, ion channel modulator, kinase inhibitor and nuclear receptor ligand. For average organic molecules, the probability is that, if the bioactivity score is more than 0 then it is active if −0.5 to 0 then moderately active [
Comp. | GPCR | ICM | KI | NRL | PI | EI |
---|---|---|---|---|---|---|
1 | 0.00 | −0.12 | −0.11 | 0.51 | 0.02 | −0.04 |
2 | 0.09 | 0.01 | −0.04 | 0.50 | 0.06 | 0.02 |
3 | 0.00 | −0.16 | −0.12 | 0.29 | −0.01 | −0.05 |
4 | 0.09 | −0.26 | −0.11 | 0.51 | 0.17 | 0.21 |
5 | −0.01 | −0.11 | −0.26 | 0.49 | 0.07 | 0.07 |
6 | 0.03 | −0.12 | −0.25 | 0.57 | 0.13 | 0.02 |
7 | −0.01 | −0.13 | −0.27 | 0.50 | 0.08 | 0.11 |
8 | −0.05 | −0.23 | −0.20 | 0.49 | 0.09 | 0.02 |
9 | 0.03 | −0.17 | −0.24 | 0.49 | 0.00 | −0.12 |
10 | 0.03 | −0.15 | −0.29 | 0.40 | 0.06 | −0.08 |
11 | 0.02 | −0.22 | −0.30 | 0.46 | 0.13 | 0.06 |
12 | −0.05 | −0.31 | −0.38 | 0.46 | 0.07 | −0.03 |
13 | −0.01 | −0.36 | −0.31 | 0.39 | 0.01 | 0.02 |
14 | −0.05 | −0.31 | −0.34 | 0.48 | 0.04 | 0.04 |
15 | 0.05 | −0.23 | −0.35 | 0.46 | 0.04 | −0.06 |
16 | 0.01 | −0.16 | −0.27 | 0.54 | 0.08 | −0.01 |
HOF | −0.36 | −0.04 | −0.25 | 0.10 | −0.28 | −0.30 |
GPCR = GPCR ligand, ICM = Ion channel modulator, KI = Kinase inhibitor, NRL = Nuclear receptor ligand, PI = Protease inhibitor and EI = Enzyme inhibitor. HOF = Hydroxyflutamide.
are expected to have near similar activity to standard drugs used based upon these four rigorous criteria (GPCR ligand, ion channel modulator, kinase inhibitor, and nuclear receptor ligand).
The toxicity risks (mutagenicity, tumorigenicity, irritation, reproduction) were calculated by the methodology developed by Osiris. The toxicity risks predictor locates fragments within a molecule, which indicates a potential toxicity risk. Toxicity risk alerts are an indication that the drawn structure may be harmful concerning the risk category specified. From the data evaluated in
The aqueous solubility (S) of a compound significantly affects its absorption and distribution characteristics. Typically, a low solubility goes along with a bad absorption, and therefore the general aim is to avoid poorly soluble compounds. Our estimated logS value is a unit stripped logarithm (base 10) of a compound’s solubility measured in mol/liter. There are more than 80% of the drugs on the market have an (estimated) logS value greater than −4. In the case of title compounds, values of logS are around −4. Further,
Compound no. | MUT | TUM | IRRIT | RE |
---|---|---|---|---|
1 | ||||
2 | ||||
3 | ||||
4 | ||||
5 | ||||
6 | ||||
7 | ||||
8 | ||||
9 | ||||
10 | ||||
11 | ||||
12 | ||||
13 | ||||
14 | ||||
15 | ||||
16 | ||||
HOF |
MUT: mutagenic; TUM: tumorigenic; IRRIT: irritant; RE: reproductive effective.
Comp. | S | DL | DS |
---|---|---|---|
1 | −4.39 | −8.360 | 0.35 |
2 | −4.14 | −9.530 | 0.38 |
3 | −4.60 | −6.810 | 0.34 |
4 | −4.60 | −6.540 | 0.32 |
5 | −3.80 | −16.98 | 0.37 |
6 | −5.09 | −9.990 | 0.30 |
7 | −4.07 | −16.39 | 0.35 |
8 | −4.82 | −10.00 | 0.33 |
9 | −4.74 | −10.02 | 0.31 |
10 | −4.33 | −9.790 | 0.32 |
11 | −4.31 | −4.530 | 0.38 |
12 | −4.65 | −4.950 | 0.21 |
13 | −4.33 | −5.150 | 0.37 |
14 | −5.05 | −2.970 | 0.27 |
15 | −5.43 | −9.330 | 0.28 |
16 | −5.43 | −9.330 | 0.28 |
HOF | −3.18 | −13.19 | 0.35 |
S: Solubility, DL: Drug likeness, DS: Drug Score.
where;
DS is the drug score. Si is the contributions calculated directly from mi LogP; logS, molecular weight and drug likeness (pi) via the second equation, which describes a spline curve. Parameters a and b are (1, −5), (1, 5), (0.012, −6) and (1, 0) for mi LogP, logS, molecular weight and drug-likeness, respectively. The ti is the contributions taken from the four toxicity risk types and the values are 1.0, 0.8 and 0.6 for no risk, medium risk and high risk, respectively. From this work, all compounds showed moderate to good drug score as compared with the standard drug used.
The Ramachandran plot analysis for androgen receptor PDB (2AX6) revealed that, the 2AX6 is an excellent choice which is in good quality to use as a target for docking studies with the title compounds. The percentage of residues in the most favored-regions was 94.1% in 2AX6 (above the cut off 75%), and the percentage of residues in additional allowed regions was 5.9% in 2AX6. This result suggests that the target enzyme’s structure was of good quality.
PASS (Prediction of Activity Spectra) [
COMP. | Androgen antagonist | Prostate cancer treatment | ||
---|---|---|---|---|
pa | pi | Pa | pi | |
1 | 0.730 | 0.003 | 0.738 | 0.004 |
2 | 0.654 | 0.004 | 0.765 | 0.004 |
3 | 0.558 | 0.004 | 0.740 | 0.004 |
4 | 0.802 | 0.003 | 0.711 | 0.005 |
5 | 0.500 | 0.005 | 0.623 | 0.005 |
6 | 0.995 | 0.002 | 0.706 | 0.004 |
7 | 0.991 | 0.002 | 0.697 | 0.004 |
8 | 0.995 | 0.002 | 0.714 | 0.004 |
9 | 0.957 | 0.002 | 0.638 | 0.005 |
10 | 0.987 | 0.002 | 0.655 | 0.005 |
11 | 0.787 | 0.003 | 0.693 | 0.007 |
12 | 0.892 | 0.002 | 0.652 | 0.005 |
13 | 0.731 | 0.003 | 0.584 | 0.005 |
14 | 0.865 | 0.003 | 0.627 | 0.005 |
15 | 0.981 | 0.002 | 0.669 | 0.004 |
16 | 0.978 | 0.002 | 0.684 | 0.004 |
HOF | 0.403 | 0.006 | 0.368 | 0.027 |
Pa = Probability of Active, Pi = Probability of Inactive, Pa > Pi confirms significant activity
Docking results between androgen receptor 2AX6 and 5,5-dimethylthiohydantoin derivatives are reported in
In order to find the active sites, the Castp Server is used. The PDB file is used as an input and the results are obtained from this tool which explains the total number of active sites present in the Query PDF file along with information on their amino acid sequence. In addition to that, it also gives their area and volume of the pockets. Pockets are empty concavities on a protein surface into which solvent (probe sphere 1.4 A) can gain access, i.e., these concavities have mouth openings connecting their interior with the outside bulk solution. Currently, shallow depressions are excluded from the calculation. In 2AX6 there are 33 pockets presented in
The interactions of each compound with the functional residues of 2AX6 demonstrated that all the ligands interact
with most of the residues in the binding pocket as shown in
Compound no. | E-value |
---|---|
1 | −283.40 |
2 | −265.67 |
3 | −271.19 |
4 | −275.11 |
5 | −264.86 |
6 | −267.75 |
7 | −263.37 |
8 | −299.54 |
9 | −277.55 |
10 | −276.51 |
11 | −262.84 |
12 | −258.33 |
13 | −264.64 |
14 | −265.53 |
15 | −263.89 |
16 | −281.81 |
HOF | −230.62 |
Pocket No | Amino Acid | position | Area | Vol |
---|---|---|---|---|
1 | LEU ,MET, GLY, VAL | 790, 787, 750, 746 | 32.00 | 16.20 |
2 | ASN, ASP, HIS, LEU | 823, 732, 729, 729 | 28.50 | 14.00 |
3 | MET, TRP, LEU, GLU | 895, 741, 712, 709 | 33.00 | 17.60 |
4 | LYS, GLN, LYS, TYR, ALA | 905, 902, 822, 739, 735 | 13.20 | 20.90 |
5 | LEU, PRO, ILE, TYR, VAL | 821, 817, 815, 739, 736 | 35.20 | 17.80 |
6 | ALA, GLN, VAL, GLY | 870, 867, 866,743 | 28.60 | 13.70 |
7 | GLU, ILE, ARG, GLN | 872, 869, 786, 783 | 30.40 | 15.70 |
8 | LEU, LEU , CYS | 838,810, 806 | 29.70 | 14.50 |
9 | PHE, PHE, LEU, ILE, LEU | 916, 856, 838, 835, 810 | 27.70 | 13.70 |
10 | ARG, ASP, GLN,ASN, ASP, HIS | 774, 695, 693, 691, 690, 689 | 30.20 | 15.10 |
11 | SER, ILE, LEU, PHE | 900, 882, 881, 878 | 30.40 | 16.90 |
12 | PHE, ASN, LEU,ASP, LEU | 827, 823, 821, 732, 728 | 27.90 | 13.70 |
13 | MET,GLN,VAL,LYS | 734,733,730, 720 | 21.40 | 14.90 |
14 | PRO, LYS,VAL,ILE,ARG | 913, 912, 911, 906, 871 | 24.50 | 16.80 |
15 | VAL, ILE, ALA, HIS, MET, TRP, | 903, 899, 877, 874, 742, 741 | 45.40 | 26.70 |
16 | SER, ARG, LEU, MET, SER, SER | 791, 788, 762, 761, 759, 753 | 35.20 | 19.30 |
17 | LEU, GLN, GLU, LEU | 805, 802, 678, 674 | 42.60 | 34.20 |
18 | PHE,ARG, TRP, ALA, GLU | 804, 752, 751, 748, 681 | 28.00 | 24.50 |
19 | MET, GLN, ILE,MET, VAL, LEU | 894, 738, 737, 734, 716, 712 | 30.50 | 25.40 |
20 | ARG, MET, GLU, ASN, ARG | 788, 775, 772, 771, 760 | 20.60 | 13.60 |
21 | ILE, VAL, GLN, ILE, HIS, TRP,TYR, GLN | 906, 903, 902, 898, 874,741, 739, 738 | 79.60 | 48.50 |
22 | GLU, ARG, GLN, SER | 872, 786, 783, 782 | 26.60 | 16.90 |
23 | TRP, GLY, GLN, SER ASN PHE | 796, 795, 792, 759, 758, 754 | 29.50 | 29.20 |
24 | ASN, LEU, GLU, PHE, ASN | 833, 830, 829, 826, 727 | 34.40 | 35.30 |
25 | ALA, LYS, LEU, TRP, GLU, LEU | 809, 808, 805, 718, 681, 677 | 73.70 | 53.80 |
26 | ILE, ARG, GLU, LEU, PHE, PRO | 841, 840, 837, 674, 673, 671 | 57.80 | 64.70 |
27 | LYS, LEU, ASP, PHE, ARG, PHE | 883, 880, 879, 876, 779, 697 | 85.00 | 57.80 |
28 | LEU, ALA, SER, ASP, PRO, GLN,ASP, HIS | 700, 699, 696, 695, 694, 693, 690, 689 | 91.00 | 68.50 |
29 | VAL,LYS, LYS, ASP, VAL, PRO, TYR | 911, 910, 905, 819, 818, 817, 739 | 62.20 | 79.60 |
30 | PHE, TYR, ILE, GLN, ASP, LEU, ARG, SER, LEU, LEU | 916, 915, 914, 867, 864, 863, 831, 814, 811, 810 | 158.7 | 114.3 |
31 | TYR, PRO, ILE, HIS, ARG, ALA, PRO, GLN, ILE, SER, LEU, LEU, GLY, SER, TYR | 915, 913, 906, 874, 871, 870, 868, 867, 815, 814, 811, 744, 743, 740, 739 | 246.9 | 236.7 |
32 | ILE, MET, PHE, LEU, ALA, PHE, LEU, ALA, PHE, LEU, MET, MET, PHE, ARG, MET, VAL, MET, MET, TRP, GLN, GLY, LEU, ASN, LEU, LEU | 899, 895, 891, 880, 877, 876, 873, 787, 780, 764, 752, 749, 746, 745, 742, 741, 711, 708, 707, 705, 704, 701 | 379.7 | 473.2 |
33 | LYS, PRO, ALA, PHE, TYR, ASN, ARG, ALA, MET, LEU, TRP, VAL, HIS, GLN, VAL, VAL, GLY, PRO, GLU | 808, 766, 765, 764, 763, 756, 752, 748, 745, 744, 718, 715, 714, 711, 685, 684, 683, 682, 681 | 347.3 | 429.8 |
the protein, but got the hydrophobic interaction with Glu793, Lys861, Leu862, Arg786, Ill869, His789, Ser865 and Lue797. Also, compound 6 had no hydrogen bond interaction with the protein, but got the hydrophobic interaction with Glu793, Lys861, His789, Ile869, Ar786, Ser865, Lue862 and Leu797. However, compound 7 was found to show three hydrogen bonds interaction with Ala735, Gln902 and Lys822 a distance of 2.61, 3.19 and 2.85 respectively, and the hydrophobic interaction with Tyr739, Lys910, Pro817, Asp732, Asp731, Asp819 and Gln738. Moreover, compound 8 had no hydrogen bond interaction with the protein, but got the hydrophobic interaction with Lys717, Val713, Met734, Glu893, Glu897, Gln738, Met894, Leu712 and Val716. However, compound 9 had no hydrogen bond interaction with the protein but got two external bonds with Val 684 and Thr755. Furthermore, this compound got hydrophobic interaction with Trp751, Asn756, Arg752, Gln711, Val685, Gly683, Glu681, Pro682, Phe804 and Ala748. On the other hand, compound 10, was found to show one hydrogen bond interaction with Gln902 a distance of 2.72 and the hydrophobic interaction with Gln738, Ala735, Asp731, Asp732, Lys822, Lys905, Val911, Asp819 and Pro817. Compound 11 had no hydrogen bond interaction with the protein, but got the hydrophobic interaction with Pro817, Lys822, Asp731, Met734, Gln738 and Ala735. On the other hand, compound 12, was found to show one hydrogen bond interaction with Ser865 a distance of 2.77 and the hydrophobic interaction with Tyr915, Asp864, Pro868, Glu793, Glu793, Gln858, Lys861, Tyr857 and Leu797. Compound 13, was found to show one hydrogen bond interaction with Gln802 a distance of 2.23, but got two external bonds with Phe804 and Thr755, and the hydrophobic interaction with Asn756, Arg752, Trp751, Glu681, Leu805, Pro801 and Glu678. However, compound 14 had no hydrogen bond interaction with the protein, but got four external bonds with Ile869, Met787, Phe794 and Leu862, also this compound got hydrophobic interaction with Arg786, Ser865, Glu793, Leu797, Ser791, Phe747, Gly 750 and Val746. However, compound 15 had no hydrogen bonds interaction with the protein, but got hydrophobic interaction with Arg786, Ser865, Glu793, Leu797, His789, Ile869, Lys861, and Leu862. On the other hand, compound 16 was found to show one hydrogen bond interaction with Trp751 a distance of 3.13, but got the hydrophobic interaction with Pro682, Gly683, Val684, Glu681, Phe804, Pro801, Leu805, Gln802 and Glu678. The interactions of hydroxyflotamide with the functional residues of 2AX6 presented in figure in (
As discussed earlier, physicochemical properties such as molecular weight MiLogP and TPSA of all a title compounds follow Lipinski’s Rule of Five. Furthermore, online software admetSAR (http://www.admetexp.org/predict/), were used to generate in silico pharmacokinetics parameters for all compounds in order to estimate their drug-like- ness properties. Various ADMET parameters are characterized for compounds 4 and hydroxyflotamide using in silico module admetSAR. The results of the analysis can be seen in
Parameter | Compound 11 (Most active) | Hydroxyflotamide | ||
---|---|---|---|---|
Absorption | Result | Probability | Result | Probability |
Blood-Brain Barrier | BBB+ | 0.8199 | BBB- | 0.8396 |
Human Intestinal Absorption | HIA+ | 0.9623 | HIA+ | 0.9625 |
Caco-2 Permeability | Caco2- | 0.6938 | Caco2- | 0.5898 |
P-glycoprotein Substrate | Non-substrate | 0.5229 | Non-substrate | 0.6835 |
P-glycoprotein Inhibitor | Non-inhibitor | 0.6193 | Non-inhibitor | 0.6634 |
Non-inhibitor | 0.9403 | Non-inhibitor | 0.8954 | |
Renal Organic Cation Transporter | Non-inhibitor | 0.8429 | Non-inhibitor | 0.9684 |
Distribution Metabolism | ||||
CYP450 2C9 Substrate | Non-substrate | 0.7697 | Non-substrate | 0.8100 |
CYP450 2D6 Substrate | Non-substrate | 0.8041 | Non-substrate | 0.8308 |
CYP450 3A4 Substrate | Non-substrate | 0.5490 | Substrate | 0.5225 |
CYP450 1A2 Inhibitor | Non-inhibitor | 0.8211 | Non-inhibitor | 0.6559 |
CYP450 2C9 Inhibitor | Non-inhibitor | 0.6976 | Inhibitor | 0.5266 |
CYP450 2D6 Inhibitor | Non-inhibitor | 0.7479 | Non-inhibitor | 0.8475 |
CYP450 2C19 Inhibitor | Non-inhibitor | 0.6359 | Inhibitor | 0.5260 |
CYP450 3A4 Inhibitor | Non-inhibitor | 0.8317 | Inhibitor | 0.5374 |
CYP Inhibitory Promiscuity | Low CYP Inhibitory Promiscuity | 0.5981 | High CYP Inhibitory Promiscuity | 0.5357 |
Excretion Toxicity | ||||
Human Ether-a-go-go-Related Gene Inhibition | Weak inhibitor | 0.9390 | Weak inhibitor | 0.9957 |
AMES Toxicity | Non AMES toxic | 0.5689 | AMES toxic | 0.5150 |
Carcinogens | Non-carcinogens | 0.6999 | Carcinogens | 0.5530 |
Fish Toxicity | High FHMT | 0.9702 | High FHMT | 0.9984 |
Tetrahymena Pyriformis Toxicity | High TPT | 0.8713 | High TPT | 0.9757 |
Honey Bee Toxicity | Low HBT | 0.8241 | Low HBT | 0.8084 |
Biodegradation | Not ready biodegradable | 0.9876 | Not ready biodegradable | 1.0000 |
Acute Oral Toxicity | III | 0.5839 | III | 0.5581 |
Carcinogenicity (Three-class) | Non-required | 0.5815 | Non-required | 0.4472 |
Acute Oral Toxicity: Category III includes compounds with LD50 values greater than 500 mg/kg but less than 5000 mg/kg. Carcinogenicity (three-class): Carcinogenic compounds with TD50 (tumorigenic dose rate 50) B10 mg/kg body wt/day were assigned as “Danger,” those with TD50 [10 mg/kg body wt/day were assigned as “Warning,” and non-carcinogenic chemicals were assigned as “Non-required.” Probability indicates scale between 0 and 1. Parameters indicating difference between the most active and the least compound have been highlighted in bold letters.
The in silico study of 5,5-dimethylthiohydantoin derivatives gives promise results for using these compounds as an androgen antagonist. The title compounds bind with more competence to the binding site of similar to hydroxyflutamide. Our study has chosen 16 molecules, which demonstrate the better result in silico analysis with better binding efficiency (in terms of docking score) towards androgen receptor than that of hydroxyflutamide. Hydroxyflotamide is a carcinogen as compared to the non-carcinogenic nature of the compound 4. On the other hand, the compound 4 is AMES non-toxic and non-carcinogens with compared to standard drug hydroxyflotamide. Hence, it has been predicted that all the title compounds can possibly act as new leads for the treatment of prostate cancer as they possess androgen antagonist activity. These results may be used in future experiments to investigate the interactions of 5,5-dimethylthiohydantoin derivatives with the androgen receptor, or may be used in vivo experiments to test their effects on the abilities of treatment of prostate cancer.
We highly grateful to professor Medhat A. Ibrahim, headmaster of Spectroscopy Department, National Research Centre, 12311, Dokki, Cairo, Egypt, for his support to achieve the molecular modeling computation.
KhaledLotfy,11, (2015) Molecular Modeling, Docking and ADMET of Dimethylthiohydantoin Derivatives for Prostate Cancer Treatment. Journal of Biophysical Chemistry,06,91-117. doi: 10.4236/jbpc.2015.64010