Combined Micellar Liquid Chromatography Technique and QSARs Modeling in Predicting the Blood–Brain Barrier Permeation of Heterocyclic Drug-like Compounds
Abstract
:1. Introduction
2. Results
3. Discussion
3.1. Chromatographic Data
3.2. In Silico Data
3.3. Establishment of Quantitative Structure–Activity Relationships
3.4. Interpretation of Descriptors
3.4.1. Lipophilicity
3.4.2. HBA
3.4.3. Molecular Size
3.4.4. Flexibility
4. Materials and Methods
4.1. Reagents and Materials
4.2. Instrumental
4.3. Chromatographic Conditions
4.4. In Silico Calculations
4.5. Statistical Analysis
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Class | General Structure | No | R1 | R2 |
---|---|---|---|---|
I | 1 | R1 = H | — | |
2 | R1 = 4-CH3 | — | ||
3 | R1 = 2-Cl | — | ||
4 | R1 = 3-Cl | — | ||
5 | R1 = 4-Cl | — | ||
6 | R1 = 3,4-Cl2 | — | ||
II | 7 | R1 = H | — | |
8 | R1 = 4-CH3 | — | ||
9 | R1 = 4-OCH3 | — | ||
10 | R1 = 4-OC2H5 | — | ||
11 | R1 = 4-Cl | — | ||
III | 12 | R1 = H | — | |
13 | R1 = 4-CH3 | — | ||
14 | R1 = 4-OCH3 | — | ||
15 | R1 = 3-Cl | — | ||
16 | R1 = 4-Cl | — | ||
17 | R1 = 3,4-Cl2 | — | ||
IV | 18 | R1 = H | — | |
19 | R1 = 2-CH3 | — | ||
20 | R1 = 4-CH3 | — | ||
21 | R1 = 2,3-(CH3)2 | — | ||
22 | R1 = 2-OCH3 | — | ||
23 | R1 = 4-OCH3 | — | ||
24 | R1 = 2-Cl | — | ||
25 | R1 = 3-Cl | — | ||
26 | R1 = 4-Cl | — | ||
27 | R1 = 3,4-Cl2 | — | ||
28 | R1 = 2,6-Cl2 | — | ||
V | 29 | R1 = H | — | |
30 | R1 = 2-CH3 | — | ||
31 | R1 = 3-CH3 | — | ||
32 | R1 = 4-CH3 | — | ||
33 | R1 = 2-OCH3 | — | ||
34 | R1 = 4-OCH3 | — | ||
35 | R1 = 4-OC2H5 | — | ||
36 | R1 = 2,3-(CH3)2 | — | ||
37 | R1 = 2-Cl | — | ||
38 | R1 = 3-Cl | — | ||
39 | R1 = 4-Cl | — | ||
40 | R1 = 3,4-Cl2 | — | ||
VI | 41 | R1 = H | R2 = H | |
42 | R1 = H | R2 = 2-Cl | ||
43 | R1 = H | R2 = 3-Cl | ||
44 | R1 = H | R2 = 4-Cl | ||
45 | R1 = 4-CH3 | R2 = H | ||
46 | R1 = 4-CH3 | R2 = 4-CH3 | ||
47 | R1 = 4-CH3 | R2 = 3-CH3 | ||
48 | R1 = 4-CH3 | R2 = 2-Cl | ||
49 | R1 = 4-CH3 | R2 = 3-Cl | ||
50 | R1 = 4-CH3 | R2 = 4-Cl | ||
51 | R1 = 4-OC2H5 | R2 = H | ||
52 | R1 = 4-OC2H5 | R2 = 4-CH3 | ||
53 | R1 = 4-OC2H5 | R2 = 2-Cl | ||
54 | R1 = 4-OC2H5 | R2 = 3-Cl | ||
55 | R1 = 4-OC2H5 | R2 = 4-Cl | ||
56 | R1 = 2-CH3 | R2 = 2-Cl | ||
57 | R1 = 4-Cl | R2 = H | ||
58 | R1 = 4-Cl | R2 = 2-Cl | ||
59 | R1 = 4-Cl | R2 = 3-Cl | ||
60 | R1 = 4-Cl | R2 = 4-Cl | ||
VII | 61 | R1 = H | — | |
62 | R1 = 4-CH3 | — | ||
63 | R1 = 2-Cl | — | ||
64 | R1 = 4-Cl | — | ||
65 | R1 = 3,4-Cl2 | — |
No | 1/km | KAM/km | R2 | No | 1/km | KAM/km | R2 |
---|---|---|---|---|---|---|---|
1 | −0.765 | 9.066 | 0.9178 | 34 | −0.329 | 3.829 | 0.9615 |
2 | −0.586 | 6.826 | 0.9530 | 35 | −0.321 | 3.685 | 0.9604 |
3 | −0.758 | 8.907 | 0.9110 | 36 | −0.432 | 5.006 | 0.9593 |
4 | −0.528 | 6.157 | 0.9700 | 37 | −0.425 | 4.933 | 0.9442 |
5 | −0.518 | 6.028 | 0.9553 | 38 | −0.425 | 4.870 | 0.9606 |
6 | −0.406 | 4.722 | 0.9748 | 39 | −0.288 | 3.326 | 0.9717 |
7 | −1.046 | 12.573 | 0.9124 | 40 | −0.214 | 2.470 | 0.9692 |
8 | −0.785 | 9.294 | 0.9592 | 41 | −0.354 | 4.119 | 0.9753 |
9 | −1.163 | 13.801 | 0.9618 | 42 | −0.289 | 3.322 | 0.9764 |
10 | −0.876 | 10.274 | 0.9477 | 43 | −0.225 | 2.944 | 0.9724 |
11 | −0.707 | 8.316 | 0.9759 | 44 | −0.246 | 2.822 | 0.9741 |
12 | −0.760 | 8.902 | 0.9302 | 45 | −0.257 | 2.976 | 0.9378 |
13 | −0.568 | 6.593 | 0.9592 | 46 | −0.206 | 2.361 | 0.9705 |
14 | −0.565 | 7.520 | 0.9932 | 47 | −0.190 | 2.198 | 0.9728 |
15 | −0.509 | 5.898 | 0.9696 | 48 | −0.199 | 2.272 | 0.9694 |
16 | −0.503 | 5.825 | 0.9732 | 49 | −0.213 | 2.448 | 0.9695 |
17 | −0.395 | 4.569 | 0.9734 | 50 | −0.174 | 2.001 | 0.9666 |
18 | −0.599 | 7.079 | 0.9622 | 51 | −0.295 | 3.399 | 0.9704 |
19 | −0.597 | 6.995 | 0.9375 | 52 | −0.211 | 2.441 | 0.9718 |
20 | −0.410 | 4.836 | 0.9776 | 53 | −0.227 | 2.606 | 0.9684 |
21 | −0.594 | 6.814 | 0.9473 | 54 | −0.285 | 3.202 | 0.9441 |
22 | −0.458 | 5.274 | 0.9638 | 55 | −0.191 | 2.203 | 0.9636 |
23 | −0.474 | 5.694 | 0.9695 | 56 | −0.309 | 3.549 | 0.9763 |
24 | −1.131 | 12.985 | 0.9193 | 57 | −0.540 | 6.358 | 0.9690 |
25 | −0.692 | 7.917 | 0.9672 | 58 | −0.180 | 2.073 | 0.9521 |
26 | −0.420 | 4.868 | 0.9733 | 59 | −0.185 | 2.118 | 0.9609 |
27 | −0.639 | 7.247 | 0.9662 | 60 | −0.157 | 1.820 | 0.9465 |
28 | −0.461 | 5.307 | 0.9593 | 61 | −0.241 | 2.856 | 0.9792 |
29 | −0.382 | 4.464 | 0.9659 | 62 | −0.175 | 2.051 | 0.9765 |
30 | −0.451 | 5.916 | 0.9656 | 63 | −0.193 | 2.343 | 0.9682 |
31 | −0.301 | 3.477 | 0.9657 | 64 | −0.151 | 1.802 | 0.9488 |
32 | −0.287 | 3.322 | 0.9707 | 65 | −0.132 | 1.550 | 0.9358 |
33 | −0.479 | 5.531 | 0.9187 |
No | log (km/KAM) | log BB | log BB* [75] | TPSA Å2 | HBD | HBA | NRB | MW g mol−1 | α Å3 | Ƥ m3 mol−1 |
---|---|---|---|---|---|---|---|---|---|---|
1 | −0.957 | 0.117 | 0.21 | 48.27 | 0 | 5 | 2 | 242.28 | 27.55 | 497.81 |
2 | −0.834 | 0.305 | 0.32 | 48.27 | 0 | 5 | 2 | 256.30 | 29.30 | 528.90 |
3 | −0.950 | 0.226 | 0.26 | 48.27 | 0 | 5 | 2 | 276.72 | 29.37 | 526.66 |
4 | −0.789 | 0.270 | 0.30 | 48.27 | 0 | 5 | 2 | 276.72 | 29.37 | 526.66 |
5 | −0.780 | 0.209 | 0.24 | 48.27 | 0 | 5 | 2 | 276.72 | 29.37 | 526.66 |
6 | −0.674 | 0.360 | 0.34 | 48.27 | 0 | 5 | 2 | 311.17 | 31.20 | 555.51 |
7 | −1.099 | −0.243 | −0.16 | 74.57 | 0 | 7 | 4 | 286.29 | 30.27 | 561.26 |
8 | −0.968 | −0.051 | −0.04 | 74.57 | 0 | 7 | 4 | 300.31 | 32.02 | 592.35 |
9 | −1.140 | −0.293 | −0.28 | 83.80 | 0 | 8 | 5 | 316.31 | 32.57 | 611.52 |
10 | −1.012 | −0.167 | −0.20 | 83.80 | 0 | 8 | 6 | 330.34 | 34.40 | 650.13 |
11 | −0.920 | −0.151 | −0.12 | 74.57 | 0 | 7 | 4 | 320.73 | 32.09 | 590.11 |
12 | −0.949 | −0.132 | −0.10 | 74.57 | 0 | 7 | 5 | 300.31 | 32.09 | 604.35 |
13 | −0.819 | 0.055 | 0.02 | 74.57 | 0 | 7 | 5 | 314.38 | 33.85 | 635.45 |
14 | −0.876 | −0.167 | −0.20 | 83.80 | 0 | 8 | 6 | 330.34 | 34.40 | 599.87 |
15 | −0.771 | 0.029 | 0.00 | 74.57 | 0 | 7 | 5 | 334.76 | 33.92 | 630.96 |
16 | −0.766 | −0.033 | −0.05 | 74.57 | 0 | 7 | 5 | 334.76 | 33.92 | 650.13 |
17 | −0.660 | 0.117 | 0.05 | 74.57 | 0 | 7 | 5 | 369.20 | 35.74 | 628.72 |
18 | −0.850 | 0.038 | 0.06 | 61.41 | 0 | 6 | 2 | 280.31 | 30.82 | 628.72 |
19 | −0.845 | 0.225 | 0.17 | 61.41 | 0 | 6 | 2 | 294.34 | 33.57 | 657.57 |
20 | −0.684 | 0.225 | 0.17 | 61.41 | 0 | 6 | 2 | 294.34 | 32.57 | 578.01 |
21 | −0.833 | 0.417 | 0.29 | 61.41 | 0 | 6 | 2 | 308.37 | 34.33 | 609.11 |
22 | −0.722 | 0.006 | −0.04 | 70.64 | 0 | 7 | 3 | 310.34 | 33.12 | 597.18 |
23 | −0.755 | 0.003 | −0.05 | 70.64 | 0 | 7 | 3 | 310.34 | 33.12 | 597.18 |
24 | −1.113 | 0.141 | 0.11 | 61.41 | 0 | 6 | 2 | 314.75 | 32.64 | 575.77 |
25 | −0.899 | 0.194 | 0.16 | 61.41 | 0 | 6 | 2 | 314.75 | 32.64 | 575.77 |
26 | −0.687 | 0.130 | 0.09 | 61.41 | 0 | 6 | 2 | 314.75 | 32.64 | 575.77 |
27 | −0.860 | 0.281 | 0.19 | 61.41 | 0 | 6 | 2 | 349.20 | 34.47 | 604.62 |
28 | −0.725 | 0.297 | 0.21 | 61.41 | 0 | 6 | 2 | 349.20 | 34.47 | 604.62 |
29 | −0.650 | 0.227 | 0.15 | 48.27 | 0 | 5 | 2 | 290.32 | 33.92 | 604.97 |
30 | −0.772 | 0.407 | 0.26 | 48.27 | 0 | 5 | 2 | 304.35 | 35.68 | 636.07 |
31 | −0.541 | 0.407 | 0.26 | 48.27 | 0 | 5 | 2 | 304.35 | 35.68 | 636.07 |
32 | −0.521 | 0.407 | 0.26 | 48.27 | 0 | 5 | 2 | 304.35 | 35.68 | 636.07 |
33 | −0.743 | 0.188 | 0.05 | 57.50 | 0 | 6 | 3 | 320.35 | 36.23 | 655.23 |
34 | −0.583 | 0.172 | 0.04 | 57.50 | 0 | 6 | 3 | 320.35 | 36.23 | 655.23 |
35 | −0.566 | 0.298 | 0.11 | 57.50 | 0 | 6 | 4 | 334.41 | 38.05 | 693.84 |
36 | −0.699 | 0.594 | 0.38 | 48.27 | 0 | 5 | 2 | 318.37 | 37.43 | 667.16 |
37 | −0.693 | 0.331 | 0.20 | 48.27 | 0 | 5 | 2 | 324.76 | 35.75 | 633.82 |
38 | −0.682 | 0.376 | 0.25 | 48.27 | 0 | 5 | 2 | 324.76 | 35.75 | 633.82 |
39 | −0.522 | 0.319 | 0.19 | 48.27 | 0 | 5 | 2 | 324.76 | 35.75 | 633.82 |
40 | −0.393 | 0.465 | 0.29 | 48.27 | 0 | 5 | 2 | 359.21 | 37.57 | 662.67 |
41 | −0.615 | 0.341 | 0.22 | 48.27 | 0 | 5 | 3 | 304.35 | 35.75 | 643.58 |
42 | −0.521 | 0.459 | 0.28 | 48.27 | 0 | 5 | 3 | 338.82 | 37.57 | 672.43 |
43 | −0.469 | 0.459 | 0.28 | 48.27 | 0 | 5 | 3 | 338.82 | 37.57 | 672.43 |
44 | −0.451 | 0.459 | 0.28 | 48.27 | 0 | 5 | 3 | 338.82 | 37.57 | 672.43 |
45 | −0.474 | 0.524 | 0.33 | 48.27 | 0 | 5 | 3 | 318.41 | 37.57 | 674.68 |
46 | −0.373 | 0.712 | 0.45 | 48.27 | 0 | 5 | 3 | 332.44 | 39.26 | 705.77 |
47 | −0.342 | 0.712 | 0.45 | 48.27 | 0 | 5 | 3 | 332.44 | 39.26 | 705.77 |
48 | −0.356 | 0.635 | 0.38 | 48.27 | 0 | 5 | 3 | 352.85 | 39.26 | 703.53 |
49 | −0.389 | 0.635 | 0.38 | 48.27 | 0 | 5 | 3 | 352.85 | 39.33 | 703.53 |
50 | −0.302 | 0.635 | 0.38 | 48.27 | 0 | 5 | 3 | 352.85 | 39.33 | 703.53 |
51 | −0.531 | 0.424 | 0.19 | 57.50 | 0 | 6 | 5 | 348.44 | 39.88 | 732.46 |
52 | −0.387 | 0.602 | 0.37 | 57.50 | 0 | 6 | 5 | 362.47 | 41.63 | 763.55 |
53 | −0.416 | 0.526 | 0.23 | 57.50 | 0 | 6 | 5 | 382.88 | 41.70 | 761.31 |
54 | −0.505 | 0.526 | 0.23 | 57.50 | 0 | 6 | 5 | 382.88 | 41.70 | 761.31 |
55 | −0.343 | 0.526 | 0.22 | 57.50 | 0 | 6 | 5 | 382.88 | 41.70 | 761.31 |
56 | −0.550 | 0.635 | 0.38 | 48.27 | 0 | 5 | 3 | 352.85 | 39.33 | 703.53 |
57 | −0.803 | 0.440 | 0.27 | 48.27 | 0 | 5 | 3 | 338.82 | 37.57 | 672.43 |
58 | −0.317 | 0.551 | 0.31 | 48.27 | 0 | 5 | 3 | 373.27 | 39.40 | 701.28 |
59 | −0.326 | 0.551 | 0.31 | 48.27 | 0 | 5 | 3 | 373.27 | 39.40 | 701.28 |
60 | −0.260 | 0.551 | 0.31 | 48.27 | 0 | 5 | 3 | 373.27 | 39.40 | 701.28 |
61 | −0.456 | 0.459 | 0.29 | 48.27 | 0 | 5 | 4 | 318.37 | 37.58 | 682.19 |
62 | −0.312 | 0.651 | 0.41 | 48.27 | 0 | 5 | 4 | 332.40 | 39.33 | 713.29 |
63 | −0.370 | 0.567 | 0.34 | 48.27 | 0 | 5 | 4 | 352.82 | 39.40 | 711.04 |
64 | −0.256 | 0.551 | 0.33 | 48.27 | 0 | 5 | 4 | 352.82 | 39.40 | 711.04 |
65 | −0.190 | 0.701 | 0.43 | 48.27 | 0 | 5 | 4 | 387.26 | 41.22 | 739.89 |
Model | R2 | R2adj | R2pred | PRESS | VIF* | SS | MSE | F | p | Q2LOO | PRESSLOO |
---|---|---|---|---|---|---|---|---|---|---|---|
M1: log BB vs. (log (km/KAM), TPSA, NRB, α) | 0.9202 | 0.9149 | 0.9088 | 0.3889 | 5.3 | 4.2636 | 0.0057 | 173.0 | 0.00000 | – | – |
M2: log BB vs. (log (km/KAM), TPSA, NRB, Ƥ) | 0.9070 | 0.9008 | 0.8931 | 0.4556 | 4.7 | 4.2636 | 0.0066 | 146.3 | 0.00000 | – | – |
M3: log BB vs. (log (km/KAM), TPSA, NRB, MW) | 0.8943 | 0.8873 | 0.8799 | 0.5119 | 5.0 | 4.2636 | 0.0075 | 129.9 | 0.00000 | – | – |
M4: log BB vs. (log (km/KAM), HBA, NRB, α) | 0.9260 | 0.9210 | 0.9150 | 0.3625 | 5.4 | 4.2636 | 0.2774 | 187.6 | 0.00000 | – | – |
M5: log BB vs. (log (km/KAM), HBA, NRB, Ƥ) | 0.9109 | 0.9049 | 0.8971 | 0.4385 | 4.7 | 4.2636 | 0.0063 | 153.3 | 0.00000 | 0.9109 | 0.4385 |
M6: log BB vs. (log (km/KAM), HBA, NRB, MW) | 0.8914 | 0.8841 | 0.8764 | 0.5268 | 4.8 | 4.2636 | 0.0077 | 123.1 | 0.00000 | – | – |
M7: log BB* vs. (log (km/KAM), TPSA, NRB, α) | 0.8523 | 0.8425 | 0.8310 | 0.3247 | 5.3 | 1.9212 | 0.0047 | 86.6 | 0.00000 | – | – |
M8: log BB* vs. (log (km/KAM), TPSA, NRB, Ƥ) | 0.8508 | 0.8409 | 0.8297 | 0.3271 | 4.7 | 1.9212 | 0.0048 | 85.5 | 0.00000 | – | – |
M9: log BB* vs. (log (km/KAM), TPSA, NRB, MW) | 0.8529 | 0.8430 | 0.8324 | 0.3219 | 5.0 | 1.9212 | 0.0047 | 86.9 | 0.00000 | – | – |
M10: log BB* vs. (log (km/KAM), HBA, NRB, α) | 0.8682 | 0.8595 | 0.8489 | 0.2904 | 5.4 | 1.9212 | 0.0042 | 98.8 | 0.00000 | – | – |
M11: log BB* vs. (log (km/KAM), HBA, NRB, Ƥ) | 0.8659 | 0.8569 | 0.8466 | 0.2941 | 4.7 | 1.9212 | 0.0043 | 96.8 | 0.00000 | 0.8659 | 0.2947 |
M12: log BB* vs. (log (km/KAM), HBA, NRB, MW) | 0.8662 | 0.8572 | 0.8473 | 0.2933 | 4.8 | 1.9211 | 0.0043 | 97.1 | 0.00000 | 0.8662 | 0.2933 |
M5*: log BB vs. (log (km/KAM), HBA, Ƥ) | 0.9087 | 0.9042 | 0.8994 | 0.4290 | 4.7 | 4.2636 | 0.2178 | 202.4 | 0.00000 | 0.9087 | 0.4290 |
M11*: log BB* vs. (log (km/KAM), HBA, Ƥ) | 0.8656 | 0.8590 | 0.8513 | 0.2858 | 4.7 | 1.9212 | 0.0042 | 131.0 | 0.00000 | 0.8656 | 0.2858 |
M12*: log BB* vs. (log (km/KAM), HBA, MW) | 0.8661 | 0.8595 | 0.8516 | 0.2852 | 4.1 | 1.9212 | 0.0042 | 131.5 | 0.00000 | 0.8515 | 0.2852 |
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Janicka, M.; Śliwińska, A.; Sztanke, M.; Sztanke, K. Combined Micellar Liquid Chromatography Technique and QSARs Modeling in Predicting the Blood–Brain Barrier Permeation of Heterocyclic Drug-like Compounds. Int. J. Mol. Sci. 2022, 23, 15887. https://doi.org/10.3390/ijms232415887
Janicka M, Śliwińska A, Sztanke M, Sztanke K. Combined Micellar Liquid Chromatography Technique and QSARs Modeling in Predicting the Blood–Brain Barrier Permeation of Heterocyclic Drug-like Compounds. International Journal of Molecular Sciences. 2022; 23(24):15887. https://doi.org/10.3390/ijms232415887
Chicago/Turabian StyleJanicka, Małgorzata, Anna Śliwińska, Małgorzata Sztanke, and Krzysztof Sztanke. 2022. "Combined Micellar Liquid Chromatography Technique and QSARs Modeling in Predicting the Blood–Brain Barrier Permeation of Heterocyclic Drug-like Compounds" International Journal of Molecular Sciences 23, no. 24: 15887. https://doi.org/10.3390/ijms232415887