As follow-up of our past publication [1] , we propose that quinolones (as part of the pyridinone family) are capable to increase the number of interactions with HIV reverse t r anscriptase (RT) or integrase (IN) by adding a halogen in position C-8 of aromatic portion of the quinolones. This addition could help with the activity of dual inhibitors of RT and IN. In this work, we add a chlorine atom with the rationale to identify in the docking simulations a halogen interaction with the oxygen in the near aminoacids in the binding pockets of RT and IN enz y mes. Our docking studies started with RT and 320 structures. Later, we took 73 structures with good results in docking with RT. The structures that we choose contain ester or acids groups in C-3 due the structural similarity with groups in charge to interact with the Mg++ ions in Elvitegravir. In conclusion, we obtained 14 structures that could occupy the allosteric pocket of RT and could inhibit the catalytic activity of IN, for this reason could be dual inhibitors. A major perspective of this work is the synthesis and testing of the potential dual inhibitors designed.
In our research group we were working with pyridinone derivates as antiretroviral against HIV-1 [
Actually, multi-halogenated compounds belong to the HAART therapy against HIV infection because they are bioactive. As an example of halogenated drugs
against HIV
The objective of this work is to propose new compounds with dual activity against RT and IN which contains halogens that contribute to the activity against HIV-1 and that could reduce the quantity of drugs to be taken orally. The infected persons have to take several pills in a treatment called HAART that have secondary effects. If the quantity of drugs is reduced, the secondary effects will be reduced and will be a benefit to the treated patients [
Based on the scheme of structures analyzed in our previous publication [
was inspired in the compounds developed by Wang et al. [
For the docking studies described below, the crystallographic structures of the biomolecular targets were retrieved from the Protein Data Bank (PDB) (http://www.rcsb.org) [
This study is a continuation of our previous results published [
Similar to the previous work [
PDB ID | Resolution (Å) | ID ligand | Co-crystalized ligand |
---|---|---|---|
2BAN (RT) | 2.95 | R157208 | |
2B5J (RT) | 2.90 | R165481 Note: the tautomeric conformation is taken | |
3L2U (IN) | 3.15 | GS9137 (Elvitegravir) |
default settings of MOE [
The flexible alignment of the new quinolones structures was performed to explore if these new structures could adopt similar conformation as the co-crystalized pyridinone analogues. Similar to our previous work, we selected a sample of 10% (32 structures) and each was aligned flexibly to the co-crystal coordinates of R157208 and R165481. For this study, the structure of the co-crystal compound was kept rigid. The docking was conducted with MOE maintaining the default settings (500 iterations in total with 30 consecutive attempts to find the best result) with the MMFF94x force field.
For this study, 320 quinolone structures were docked with the crystallographic structures PDB ID: 2BAN and 2B5J [
For73 structures were selected based on the similarity with the functional groups and binding poses with known dual inhibitors of RT and IN. The 73 structures were docked with the crystallographic structure PDB ID: 3L2U with the same parameters used in the docking of the crystal ligand (Elvitegravir, GS9137) [
In order to explore the potential oral bioavailability of the structures proposed, we calculated the pharmaceutical properties molecular weight (MW), the partition coefficient octanol/water (Log P) as a measure of lipophilicity, topological polar surface area (TPSA), number of hydrogen bond donors (HBD), number of hydrogen bond acceptors (HBA), and number of rotatable bonds (RB) [
The coordinates obtained in our previous work [
Before docking the newly structures proposed in this work (
A sample of 10% of the data (32 structures) was taken of the 320 structures in a scheme of stratified random sampling. The structures were aligned flexibly with the position of crystallographic structures of R157208 and R165481 (
After the docking assay performed with MOE for 320 new molecules using PDB ID: 2BAN, we select 72 structures maintaining interaction with important aminoacids for this investigation. The contacts of interest observed were between the substituent in C-4 of each molecule with Tyr188 and the conserved aminoacids Trp229; and the interaction of substituent in C-3 with conserved aminoacid Pro236 due to a 180˚ rotation of the molecule but always maintaining the characteristic interaction of pyridinones and other non-nucleoside RT inhibitors [
Also, is important to indicate that as result of docking we could identify some structures with double interaction with aminoacids of interest because at the same time show the possibility to have contacts with Pro236 and Tyr188 (structures 152 and 181); and contacts with Pro236 and Trp229 observed in the structures 123 and 158 (
In general,
Structures with multiple interactions with aminoacids of interest have better possibilities as inhibitors according with the docking with 2BAN.
The results of docking of 320 structures with PDB ID: 2B5J helped us to identify
64 structures with contact with aminoacids of interest as Trp229, Pro236, Tyr181 and Tyr188. The average of score as result of the docking was −7.0418 with a standard deviation of 0.897 in this study. Taking in count the average and the standard deviation, there are 10 outstanding molecules and seven molecules with lower priority (
Docking with the structure PDB ID: 2B5J revealed that compounds 7 and 33 have the possibility to interact with two aminoacids simultaneously with the substituent in C-4 that can confer to the ligands maintain activity against RT.
Another interesting interaction that we observed in docking with quinolones 266 and 270 was a halogen interaction between Iodine and Pro236 as is shown in
In the docking performed with PDB ID: 2B5J we could observe less halogen interactions than the docking with PDB ID: 2BAN. The contacts with chlorine in position C-8 are with Lys103. This kind of contact helps to fix the quinolone to
# OF STRUCTURE | SCORES | INTERACTIONS | Halogen in C-8 (interaction) |
---|---|---|---|
2 | −6.479 | Tyr188 | |
3 | −6.783 | Trp229 | |
18 | −7.452 | Tyr188 | |
26 | −7.177 | Pro236 | |
41 | −6.919 | Trp229 | |
42 | −6.990 | Tyr188 | |
47 | −6.829 | Trp229 | |
48 | −6.826 | Trp229 | |
58 | −7.128 | Tyr188 | |
68 | −8.456 | Trp229 | |
72 | −7.330 | Tyr188 | |
82 | −6.376 | Tyr188 | |
83 | −6.870 | Trp229 | |
88 | −7.199 | Tyr188 | |
91 | −7.619 | Tyr188 | |
92 | −6.139 | Tyr188 | |
96 | −7.570 | Tyr188 | |
97 | −7.624 | Tyr188 | |
99 | −7.000 | Tyr188 | |
101 | −7.712 | Tyr188 | |
102 | −7.918 | Tyr188 | |
104 | −5.847 | Pro236 | Cl-Pro236 |
107 | −7.074 | Tyr188 | |
108 | −6.691 | Tyr188 | |
118 | −6.832 | Trp229 | |
122 | −7.624 | Tyr188 | |
123 | −7.175 | Pro236, Trp229 | Cl-Pro236 |
128 | −6.959 | Trp229 | |
133 | −7.206 | Trp229 | |
134 | −7.389 | Pro236 | Cl-Pro236 |
138 | −5.878 | Trp229 | |
145 | −6.753 | Pro236 | Cl-Pro236 |
146 | −7.673 | Pro236 | |
147 | −7.355 | Pro236 | |
148 | −6.299 | Tyr188 |
151 | −7.517 | Pro236 | Cl-Pro236 |
---|---|---|---|
152 | −7.827 | Pro236, Tyr188 | Cl-Pro236 |
153 | −6.938 | Pro236 | Cl-Pro236 |
158 | −6.617 | Pro236, Trp229 | Cl-Pro236 |
161 | −7.501 | Pro236, Tyr188 | Cl-Pro236 |
167 | −5.387 | Tyr188 | |
169 | −6.688 | Pro236 | Cl-Pro236 |
170 | −6.265 | Pro236 | Cl-Pro236 |
178 | −4.414 | Pro236 | Cl-Pro236 |
181 | −7.821 | Pro236, Tyr188 | Cl-Pro236 |
182 | −8.168 | Tyr188 | |
184 | −7.015 | Pro236 | Cl-Pro236 |
186 | −6.999 | Pro236 | Cl-Pro236 |
187 | −7.315 | Pro236 | Cl-Pro236 |
191 | −6.400 | Tyr188 | |
192 | −7.287 | Pro236 | Cl-Pro236 |
193 | −6.334 | Trp229 | |
196 | −7.542 | Pro236, Tyr188 | Cl-Pro236 |
197 | −7.623 | Pro236, Tyr188 | Cl-Pro236 |
200 | −7.296 | Pro236 | Cl-Pro236 |
202 | −7.401 | Pro236, Tyr188 | Cl-Pro236 |
203 | −6.739 | Pro236 | Cl-Pro236 |
206 | −6.478 | Pro236 | Cl-Pro236 |
212 | −5.214 | Pro236 | Cl-Pro236 |
213 | −4.406 | Pro236, Tyr188, Trp229 | Cl-Pro236 |
228 | −6.818 | Tyr188 | |
253 | −7.483 | Trp229 | |
268 | −6.996 | Tyr188 | |
276 | −7.190 | Tyr188 | |
281 | −6.829 | Pro236 | Cl-Pro236 |
287 | −6.219 | Trp229 | |
292 | −6.241 | Pro236 | Cl-Pro236 |
295 | −6.051 | Pro236 | Cl-Pro236 |
308 | −4.996 | Trp229 | |
310 | −6.887 | Pro236 | Cl-Pro236 |
312 | −6.015 | Tyr188 | |
316 | −5.927 | Pro236 | Cl-Pro236 |
Average | −6.861 | ||
Std. Dev. | 0.784 |
# OF STRUCTURE | SCORES | INTERACTIONS | Halogen In C-8 (interaction) |
---|---|---|---|
1 | −7.163 | Trp229 | |
2 | −7.085 | Trp229 | |
7 | −7.774 | Tyr229, Tyr188 | |
13 | −8.080 | Trp229 | |
16 | −7.039 | Pro236 | |
20 | −6.898 | Pro236 | |
23 | −8.864 | Trp229 | |
28 | −6.865 | Trp229 | |
32 | −7.392 | Tyr181 | |
33 | −7.163 | Tyr181, Tyr188 | |
36 | −8.461 | Trp229 | |
37 | −8.711 | Trp229 | |
38 | −7.273 | Tyr181 | |
41 | −7.845 | Trp229 | |
43 | −6.631 | Tyr181 | |
46 | −7.915 | Trp229 | |
47 | −7.146 | Trp229 | |
48 | −8.002 | Trp229 | |
49 | −6.942 | Trp229 | |
52 | −7.784 | Trp229 | |
53 | −7.053 | Tyr181 | |
57 | −6.362 | Tyr188 | |
58 | −7.461 | Trp229 | Cl-Lys103 |
59 | −6.584 | Tyr188 | |
60 | −5.427 | Pro236 | |
61 | −6.362 | Tyr188 | |
77 | −6.965 | Tyr181 | |
78 | −8.207 | Trp229 | |
91 | −7.605 | Trp229 | |
93 | −7.175 | Trp229 | |
102 | −7.124 | Tyr188 | |
103 | −5.788 | Tyr181 | |
111 | −7.379 | Trp229 |
115 | −6.411 | Pro236 | |
---|---|---|---|
122 | −6.569 | Trp229 | |
123 | −5.635 | Pro236 | |
128 | −9.083 | Trp229 | |
132 | −6.562 | Tyr181 | Cl-Lys103 |
133 | −6.874 | Trp229 | |
136 | −6.509 | Tyr181 | Cl-Lys103 |
138 | −8.164 | Trp229 | |
143 | −6.764 | Pro236, Tyr188 | |
146 | −6.970 | Tyr188 | |
148 | −8.160 | Trp229 | |
158 | −6.884 | Tyr181 | |
167 | −6.683 | Tyr181 | |
171 | −7.547 | Trp229 | |
173 | −5.778 | Pro236 | |
183 | −3.913 | Pro236 | |
198 | −6.562 | Trp229 | |
202 | −7.060 | Pro236 | |
203 | −6.023 | Pro236 | |
208 | −6.719 | Trp229 | |
221 | −7.194 | Tyr188 | |
228 | −6.645 | Tyr188 | |
232 | −6.878 | Trp229 | |
243 | −7.253 | Tyr188 | |
255 | −7.056 | Tyr188 | |
258 | −6.774 | Trp229 | Cl-Lys103 |
260 | −6.999 | Tyr188 | |
263 | −7.325 | Trp229 | |
266 | −6.424 | I-Pro236 | |
270 | −6.988 | I-Pro236 | |
288 | −8.382 | Trp229 | |
Average | −7.083 | ||
Std. Dev. | −0.854 |
the allosteric site and the flexibility of the substituent in C-4 let the ligand to make contact with Tyr181 or Trp229 (
Another interesting result was observed with the docking of 143 (
which at same time show interaction with Tyr188 and pro236 with C-4 and C-3 substituents respectively. So, if the interaction with Tyr188 is lost because a mutation the compound could maintain activity against RT because Pro236, which is an aminoacid, conserved.
We found 21 structures that coincide in
# OF STRUCTURE | INTERACTIONS: PDB ID: 2BAN | INTERACTIONS: PDB ID: 2B5J | Halogen in C-8 (interaction) |
---|---|---|---|
2 | Trp229 | Tyr188 | |
41 | Trp229 | Trp229 | |
47 | Trp229 | Trp229 | |
48 | Trp229 | Trp229 | |
58 | Trp229 | Tyr188 | |
91 | Trp229 | Tyr188 | |
102 | Tyr188 | Tyr188 | |
122 | Trp229 | Tyr188 | |
123 | Pro236 | Pro236, Trp229 | Cl-Pro236 |
128 | Trp229 | Trp229 | |
133 | Trp229 | Trp229 | |
134 | Tyr188 | Pro236 | Cl-Pro236 |
138 | Trp229 | Trp229 | |
146 | Tyr188 | Pro236 | |
148 | Trp229 | Tyr188 | |
158 | Tyr181 | Pro236, Trp229 | |
167 | Tyr181 | Tyr188 | |
192 | Tyr188 | Pro236 | Cl-Pro236 |
202 | Pro236 | Pro236, Tyr188 | Cl-Pro236 |
203 | Pro236 | Pro236 | Cl-Pro236 |
228 | Tyr188 | Tyr188 |
shown the 21 structures and the aminoacid of contact depending of PDB structure of RT.
In order to validate the docking with IN, we re-docked the co-crystal ligand in PDB ID: 3L2U (
We docked 73 selected quinolone structures that showed key interactions in the docking models with PDB ID: 2BAN and 2B5J, respectively. The docking with IN was done with the structure of IN PDB ID: 3L2U (Structures of quinolones in supplementary material as
ID | Score |
---|---|
42 | −5.865 |
46 | −6.503 |
47 | −5.670 |
82 | −4.031 |
83 | −6.497 |
91 | −5.970 |
102 | −5.834 |
111 | −6.609 |
138 | −6.686 |
151 | −6.387 |
152 | −6.081 |
169 | −5.104 |
213 | −6.301 |
232 | −6.044 |
Average | −5.999 |
Std. Dev. | 0.686 |
summarized the results of 14 structures with potential to be dual inhibitors of RT and IN.
In
The less favorable result in docking with 3L2U is for quinolone 82 because have a score of −4.031. The distances between oxygens in quinolone and the Mg++ ions have an average of 2.6 Å. The
As result of the entire analysis of docking with RT and IN we got 14 quinolones that could act like dual inhibitors. In
The structures identified as potential compounds with activity against RT and IN were evaluated in base to the rules of Lipinski and Veber, which comprise six pharmacological properties of interest. The pharmacological properties calculated to 73 structures were MW, Log P, HBD and HBA, RB and TPSA. The results are included in supplementary material (
The results of docking with RT reveal in MOE that chlorine in C-8 of the quinolone could has the capacity to interact with Pro236 or Lys103 forming a halogen bond. The most important halogen interaction is with an oxygen atom of the carbonyl group of Pro236. Pro236 is a conserved aminoacid that could contribute to the inhibition activity of RT even help to preserve the activity with
mutant strains of HIV. After analysis of the docking results of 320 quinolone structures with PDB ID: 2BAN, 2B5J and 3L2U, 14 structures were identified with possible dual activity in inhibition of RT and IN. There was not any halogen interaction between the 14 structures and IN. The most promising compounds to be synthetized are the quinolones 138, 111, 46, 83 and 151 (
The main perspective of this work is synthetizing the structures proposed in this work and perform their biological evaluation (assays of cytotoxicity and inhibition of the activity of RT and IN) with the purpose of verifying the computational results.
A.C.V. is grateful to CONACyT and UNAM for the postdoctoral scholarship #291222. This work was supported by the Instituto de Investigaciones Biomédicas, UNAM through the program Nuevas Alternativas de Tratamiento para Enfermedades Infecciosas (Novel Alternatives for the Treatment of Infection Diseases) (NUATEI-IIB-UNAM), and Programa de Apoyo a la Investigación y el Posgrado (PAIP) grant 5000-9163, Facultad de Química, UNAM.
The authors declare no conflicts of interest regarding the publication of this paper.
Cabrera, A., Hernández, L.H., Chávez, D. and Medina-Franco, J.L. (2018) Molecular Modeling of Quinoline-Based Compounds as Potential Dual Inhibitors of Reverse Transcriptase and Integrase of HIV. Computational Molecular Bioscience, 8, 122-148. https://doi.org/10.4236/cmb.2018.83007
ID | R157208 | R165481 |
---|---|---|
10 | −72.1146 | −83.9869 |
20 | −86.0508 | −81.9987 |
30 | −77.5192 | −84.8052 |
40 | −85.4631 | −92.0709 |
50 | −74.1501 | −96.4579 |
60 | −86.5782 | −88.9039 |
70 | −83.6632 | −93.2938 |
80 | −93.4436 | −74.8226 |
90 | −70.14 | −97.9708 |
100 | −76.3413 | −80.4863 |
110 | −103.698 | −93.2389 |
120 | −76.968 | −89.1745 |
130 | −77.801 | −81.0855 |
140 | −64.038 | −100.687 |
150 | −90.5816 | −77.0796 |
160 | −85.6552 | −87.0859 |
170 | −104.058 | −92.3016 |
180 | −79.5108 | −83.4159 |
190 | −84.9452 | −72.8596 |
200 | −75.2163 | −85.3578 |
210 | −83.6687 | −86.5658 |
220 | −82.4579 | −82.4668 |
230 | −65.9072 | −91.0722 |
240 | −80.5505 | −77.274 |
250 | −75.0684 | −72.0681 |
260 | −66.0169 | −63.9789 |
270 | −79.3474 | −83.7659 |
280 | −78.3733 | −62.4943 |
290 | −69.3394 | −99.2574 |
300 | −86.3217 | −91.1956 |
310 | −68.563 | −53.3706 |
320 | −78.0818 | −68.356 |
Average | −80.051 | −83.4046 |
Std. Dev. | 9.583484 | 11.1369 |
# of Structure | MW | log P | HBD | HBA | RB | TPSA | # of Structure | MW | log P | HBD | HBA | RB | TPSA |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
1 | 348.83 | 4.5 | 2 | 3 | 6 | 71.4 | 122 | 365.81 | 3.7 | 1 | 4 | 6 | 76.1 |
2 | 349.81 | 3.9 | 1 | 3 | 6 | 64.6 | 123 | 379.84 | 4.1 | 1 | 4 | 7 | 76.1 |
3 | 363.84 | 4.3 | 1 | 3 | 7 | 64.6 | 128 | 365.81 | 3.7 | 1 | 4 | 7 | 76.1 |
7 | 335.79 | 4.1 | 1 | 4 | 6 | 68.7 | 132 | 370.23 | 4.8 | 1 | 4 | 6 | 68.7 |
13 | 335.79 | 4.1 | 1 | 4 | 6 | 68.7 | 133 | 379.84 | 4.1 | 1 | 4 | 7 | 76.1 |
16 | 306.75 | 3.7 | 4 | 4 | 4 | 82.4 | 134 | 322.7 | 1.9 | 1 | 5 | 6 | 99.9 |
18 | 321.76 | 3.5 | 3 | 4 | 5 | 75.6 | 136 | 355.22 | 4.4 | 2 | 3 | 5 | 71.4 |
20 | 304.69 | 2.8 | 3 | 6 | 5 | 103.4 | 138 | 337.76 | 3.2 | 3 | 5 | 5 | 87.1 |
32 | 365.81 | 3.7 | 1 | 4 | 6 | 76.1 | 143 | 356.2 | 4.7 | 3 | 5 | 5 | 79.7 |
33 | 379.84 | 4.1 | 1 | 4 | 7 | 76.1 | 151 | 443.73 | 4.1 | 2 | 3 | 6 | 78.9 |
36 | 350.8 | 2.9 | 2 | 3 | 6 | 78.9 | 152 | 444.71 | 4.5 | 1 | 4 | 6 | 76.1 |
37 | 351.79 | 3.3 | 1 | 4 | 6 | 76.1 | 153 | 458.74 | 4.9 | 1 | 4 | 7 | 76.1 |
38 | 365.81 | 3.7 | 1 | 4 | 7 | 76.1 | 161 | 429.7 | 3.7 | 2 | 3 | 6 | 78.9 |
41 | 413.7 | 3.9 | 2 | 2 | 6 | 67.4 | 167 | 416.66 | 3.7 | 1 | 4 | 5 | 76.1 |
42 | 414.68 | 4.3 | 1 | 3 | 6 | 64.6 | 169 | 401.6 | 2.7 | 1 | 5 | 6 | 99.9 |
43 | 351.79 | 3.3 | 1 | 4 | 6 | 76.1 | 170 | 413.61 | 2.8 | 1 | 5 | 6 | 99.9 |
46 | 322.75 | 2.4 | 4 | 4 | 4 | 89.9 | 171 | 357.19 | 3.1 | 4 | 4 | 4 | 89.9 |
47 | 400.66 | 3.9 | 1 | 3 | 5 | 64.6 | 173 | 372.2 | 3.9 | 3 | 5 | 5 | 87.1 |
48 | 414.68 | 4.3 | 1 | 3 | 6 | 64.6 | 181 | 399.27 | 3.9 | 2 | 3 | 6 | 78.9 |
49 | 308.68 | 1.8 | 3 | 6 | 5 | 110.9 | 182 | 400.26 | 4.4 | 1 | 4 | 6 | 76.1 |
61 | 427.73 | 5.3 | 2 | 3 | 6 | 71.4 | 183 | 489.74 | 5.5 | 1 | 4 | 7 | 68.7 |
72 | 370.23 | 4.2 | 1 | 3 | 6 | 64.6 | 184 | 385.2 | 3.3 | 1 | 5 | 7 | 99.9 |
77 | 400.66 | 4.5 | 1 | 4 | 5 | 68.7 | 191 | 385.25 | 3.6 | 2 | 3 | 6 | 78.9 |
78 | 414.68 | 4.9 | 1 | 4 | 6 | 68.7 | 192 | 386.23 | 4 | 1 | 4 | 6 | 76.1 |
82 | 342.18 | 3.7 | 3 | 4 | 4 | 75.6 | 193 | 400.26 | 4.4 | 1 | 4 | 7 | 76.1 |
83 | 356.2 | 4.1 | 3 | 4 | 5 | 75.6 | 196 | 371.22 | 3.2 | 2 | 3 | 5 | 78.9 |
91 | 474.73 | 4.1 | 2 | 2 | 6 | 67.4 | 197 | 372.2 | 3.6 | 1 | 4 | 5 | 76.1 |
92 | 475.71 | 4.5 | 1 | 3 | 6 | 64.6 | 198 | 461.68 | 4.7 | 1 | 4 | 6 | 68.7 |
93 | 458.74 | 4.9 | 1 | 4 | 7 | 76.1 | 200 | 369.16 | 2.7 | 1 | 5 | 6 | 99.9 |
101 | 460.7 | 3.7 | 2 | 2 | 6 | 67.4 | 202 | 358.18 | 3.5 | 3 | 5 | 4 | 87.1 |
102 | 461.68 | 4.2 | 1 | 3 | 6 | 64.6 | 203 | 372.2 | 3.9 | 3 | 5 | 5 | 87.1 |
103 | 444.71 | 4.5 | 1 | 4 | 7 | 76.1 | 212 | 491.71 | 4.3 | 1 | 4 | 6 | 76.1 |
104 | 446.63 | 3.1 | 1 | 4 | 7 | 88.4 | 213 | 505.74 | 4.7 | 1 | 4 | 7 | 76.1 |
107 | 447.66 | 3.8 | 1 | 3 | 5 | 64.6 | 221 | 476.7 | 3.5 | 2 | 3 | 6 | 78.9 |
108 | 461.68 | 4.2 | 1 | 3 | 6 | 64.6 | 228 | 477.68 | 3.9 | 1 | 4 | 6 | 76.1 |
111 | 401.64 | 3.2 | 4 | 4 | 4 | 89.9 | 232 | 449.63 | 3.5 | 3 | 5 | 4 | 87.1 |
115 | 399.58 | 2.7 | 3 | 6 | 5 | 110.9 | |||||||
Specification | <500 | <5 | <5 | <10 | <10 | <140 | Specification | <500 | <5 | <5 | <10 | <10 | <140 |