QSPR/QSAR: State-of-Art, Weirdness, the Future
Abstract
:1. Introduction
- Be associated with a defined endpoint of regulatory importance;
- Take the form of an unambiguous algorithm;
- Have a clear domain of applicability;
- Be associated with appropriate measures of goodness of robustness, and predictivity;
- Have a mechanistic interpretation.
2. QSPR/QSAR: State-of-Art
2.1. The First Weirdness of QSPR/QSAR
2.2. The Second Weirdness of QSPR/QSAR
2.3. The Third Weirdness of QSPR/QSAR
3. Discussion
3.1. Multi-target QSAR Models
3.2. Similarity of Endpoints
3.2.1. Mutagenicity
3.2.2. Anticancer Activity
3.2.3. Blood–Brain Barrier (BBB)
3.3. Gender-Oriented QSAR Models
3.4. The Simplicity or the Efficiency: Which is Better?
4. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Sample Availability: Samples of the compounds are not available from the authors. |
Split #1 | Training set = 1, 4, 6, 7, 8, 9, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 23, 25, 27, 29, 30, 31, 33, 34, 36, 37, 38, 40, 41, 42, 45, 46, 48, 51, 52, 54, 55, 56, 57, 59, 60, 61, 63, 64, 65, 67, 69, 70, 73, 74, 75, 77, 90, 94, 98, 99, 109, 112, 116, 117, 118, 120, 121, 122, 123, 124, 126, 130, 136; Validation set = 2, 3, 5, 10, 11, 22, 26, 32, 35, 39, 43, 47, 68, 71, 92, 103, 125, 143 |
Split #2 | Training set = 1, 6, 7, 8, 9, 12, 13, 14, 15, 16, 18, 19, 23, 25, 27, 31, 33, 34, 36, 40, 41, 42, 45, 46, 48, 51, 54, 55, 56, 57, 59, 61, 63, 65, 67, 69, 73, 74, 75, 77, 98, 109, 112, 116, 117, 121, 123, 124, 130, 136, 5, 10, 11, 22, 26, 32, 39, 43, 47, 68, 71, 92, 103, 125, 143; Validation set = 4, 17, 20, 21, 29, 30, 37, 38, 52, 60, 64, 70, 90, 94, 99, 118, 120, 122, 126, 2, 3, 35 |
Split #3 | Training set = 1, 4, 6, 7, 8, 9, 12, 13, 14, 15, 16, 17, 18, 19, 21, 23, 25, 27, 29, 31, 36, 37, 38, 40, 41, 42, 45, 48, 51, 54, 56, 57, 59, 60, 64, 65, 69, 70, 73, 74, 75, 77, 94, 98, 99, 109, 116, 118, 121, 124, 130, 136, 2, 5, 10, 11, 26, 32, 35, 39, 43, 47, 68, 71, 125, 143; Validation set = 20, 30, 33, 34, 46, 52, 55, 61, 63, 67, 90, 112, 117, 120, 122, 123, 126, 3, 22, 92, 103 |
Method | Split | Number of Compounds in Validation Set | Determination Coefficient for Validation Set |
---|---|---|---|
3D-QSAR [60] | #1 | 18 | 0.77 |
Method 1 | #1 | 18 | 0.43 |
Method 2 | #1 | 18 | 0.53 |
Method 1 | #2 | 22 | 0.84 |
Method 1 | #3 | 21 | 0.81 |
Method 2 | #2 | 22 | 0.82 |
Method 2 | #3 | 21 | 0.85 |
SMILES Attribute | Comments |
---|---|
Sk | One symbol or two symbols which cannot be examined separately in SMILES, e.g., Cl, Br, etc. |
SSk | A combination of two connected Sk |
BOND | Descriptor reflects the presence in SMILES of the following symbols: ‘@’, ‘=’, and ‘#’ (i.e. presence of different bonds) |
NOSP | Descriptor reflects the presence of the following chemical elements nitrogen (i.e., symbol ‘N’), oxygen (i.e., symbols ‘O’), Sulfur (i.e., symbol ‘S’), and phosphorus (i.e., symbol ‘P’) |
HALO | Descriptor reflects the presence of fluorine (i.e., symbol ‘F’), chlorine (i.e., symbols ‘Cl’), bromine (i.e., symbols ‘Br’), and iodine (i.e., ‘I’) |
PAIR | Descriptor reflects simultaneous the presence of pair of the above elements (i.e. details related to BOND, NOSP, and HALO, without any details about their places in molecular structure) |
ID | Attribute | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
1 | Sk | C | l | . | . | . | . | . | . | . | . | . | . |
c | . | . | . | . | . | . | . | . | . | . | . | ||
1 | . | . | . | . | . | . | . | . | . | . | . | ||
c | . | . | . | . | . | . | . | . | . | . | . | ||
c | . | . | . | . | . | . | . | . | . | . | . | ||
( | . | . | . | . | . | . | . | . | . | . | . | ||
C | l | . | . | . | . | . | . | . | . | . | . | ||
(* | . | . | . | . | . | . | . | . | . | . | . | ||
c | . | . | . | . | . | . | . | . | . | . | . | ||
c | . | . | . | . | . | . | . | . | . | . | . | ||
c | . | . | . | . | . | . | . | . | . | . | . | ||
1 | . | . | . | . | . | . | . | . | . | . | . | ||
C | . | . | . | . | . | . | . | . | . | . | . | ||
( | . | . | . | . | . | . | . | . | . | . | . | ||
O | . | . | . | . | . | . | . | . | . | . | . | ||
( | . | . | . | . | . | . | . | . | . | . | . | ||
= | . | . | . | . | . | . | . | . | . | . | . | ||
O | . | . | . | . | . | . | . | . | . | . | . | ||
2 | SSk | c | . | . | . | C | l | . | . | . | . | . | . |
c | . | . | . | 1 | . | . | . | . | . | . | . | ||
c | . | . | . | 1 | . | . | . | . | . | . | . | ||
c | . | . | . | c | . | . | . | . | . | . | . | ||
c | . | . | . | ( | . | . | . | . | . | . | . | ||
C | l | . | . | ( | . | . | . | . | . | . | . | ||
C | l | . | . | ( | . | . | . | . | . | . | . | ||
c | . | . | . | ( | . | . | . | . | . | . | . | ||
c | . | . | . | c | . | . | . | . | . | . | . | ||
c | . | . | . | c | . | . | . | . | . | . | . | ||
c | . | . | . | 1 | . | . | . | . | . | . | . | ||
c | . | . | . | 1 | . | . | . | . | . | . | . | ||
C | . | . | . | 1 | . | . | . | . | . | . | . | ||
O | . | . | . | ( | . | . | . | . | . | . | . | ||
O | . | . | . | ( | . | . | . | . | . | . | . | ||
= | . | . | . | ( | . | . | . | . | . | . | . | ||
= | . | . | . | = | . | . | . | . | . | . | . | ||
3 | BOND | B | O | N | D | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
4 | NOSP | N | O | S | P | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
5 | HALO | H | A | L | O | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
6 | PAIR | + | + | + | + | C | l | . | . | O | = | = | = |
+ | + | + | + | C | l | . | . | B | 2 | = | = | ||
+ | + | + | + | O | . | . | . | B | 2 | = | = |
Attributes, SAk | m1.1 | m1.2 | m1.3 | m2.1 | m2.2 | m2.3 | |
---|---|---|---|---|---|---|---|
Mutagenicity (#1) vs. Anticancer Activity (#2) | |||||||
1 | 1........... | + | + | + | + | + | + |
2 | c...2....... | + | + | + | + | + | + |
3 | c...(....... | + | + | + | + | + | + |
4 | 3........... | + | + | + | + | + | + |
5 | C........... | + | + | + | + | + | + |
6 | 1...(....... | + | + | + | + | + | + |
7 | C...1....... | + | + | + | + | + | + |
8 | C...3....... | + | + | + | + | + | + |
9 | Cl..(....... | + | + | + | + | + | + |
10 | Cl.......... | + | + | + | + | + | + |
1 | c........... | + | + | + | − | − | − |
2 | O........... | + | + | + | − | − | − |
3 | O...(....... | + | + | + | − | − | − |
4 | N...(....... | − | − | − | + | + | + |
5 | ++++N---O=== | − | − | − | + | + | + |
6 | NOSP11000000 | − | − | − | + | + | + |
7 | C...(....... | − | − | − | + | + | + |
8 | C...C....... | − | − | − | + | + | + |
Mutagenicity (#1) vs. BBB (#2) | |||||||
1 | 1........... | + | + | + | + | + | + |
2 | BOND00000000 | + | + | + | + | + | + |
3 | HALO00000000 | + | + | + | + | + | + |
4 | NOSP10000000 | + | + | + | + | + | + |
5 | 1...(....... | + | + | + | + | + | + |
6 | ++++CL--N=== | + | + | + | + | + | + |
7 | -........... | + | + | + | + | + | + |
8 | =...(....... | + | + | + | + | + | + |
9 | C...1....... | + | + | + | + | + | + |
10 | BOND10000000 | + | + | + | + | + | + |
11 | Cl..(....... | + | + | + | + | + | + |
12 | Cl.......... | + | + | + | + | + | + |
13 | N...+....... | + | + | + | + | + | + |
14 | N........... | − | − | − | − | − | − |
1 | O........... | + | + | + | − | − | − |
2 | O...(....... | + | + | + | − | − | − |
3 | N...1....... | + | + | + | − | − | − |
4 | [...+....... | + | + | + | − | − | − |
5 | NOSP11000000 | − | − | − | + | + | + |
6 | C...(....... | − | − | − | + | + | + |
7 | C...C....... | − | − | − | + | + | + |
BBB (#1) vs. anticancer activity (#2) | |||||||
1 | C...C....... | + | + | + | + | + | + |
2 | C...(....... | + | + | + | + | + | + |
3 | 1........... | + | + | + | + | + | + |
4 | C...1....... | + | + | + | + | + | + |
5 | C...=....... | + | + | + | + | + | + |
6 | ++++N---B2== | + | + | + | + | + | + |
7 | C...2....... | + | + | + | + | + | + |
8 | NOSP11000000 | + | + | + | + | + | + |
9 | 1...(....... | + | + | + | + | + | + |
10 | O...C....... | + | + | + | + | + | + |
11 | 2...(....... | + | + | + | + | + | + |
12 | 4........... | + | + | + | + | + | + |
13 | Cl.......... | + | + | + | + | + | + |
14 | Cl..(....... | + | + | + | + | + | + |
15 | ++++S---B2== | + | + | + | + | + | + |
16 | HALO01000000 | + | + | + | + | + | + |
17 | ++++F---B2== | + | + | + | + | + | + |
18 | ++++F---N=== | + | + | + | + | + | + |
19 | HALO10000000 | + | + | + | + | + | + |
20 | N...4....... | + | + | + | + | + | + |
21 | ++++CL--S=== | + | + | + | + | + | + |
22 | (........... | − | − | − | − | − | − |
23 | O........... | − | − | − | − | − | − |
24 | O...(....... | − | − | − | − | − | − |
25 | 5........... | − | − | − | − | − | − |
26 | C...5....... | − | − | − | − | − | − |
1 | ++++Cl--B2== | + | + | + | − | − | − |
2 | F...(....... | + | + | + | − | − | − |
3 | ++++F---Cl== | + | + | + | − | − | − |
4 | ++++O---B2== | − | − | − | + | + | + |
5 | 2........... | − | − | − | + | + | + |
6 | =...2....... | − | − | − | + | + | + |
7 | 3...(....... | − | − | − | + | + | + |
8 | ++++O---S=== | − | − | − | + | + | + |
Similarity | |||
---|---|---|---|
Mutagenicity | Anticancer Activity | Blood–Brain Barrier | |
Mutagenicity | 41 | 10 | 14 |
Anticancer activity | 10 | 61 | 26 |
Blood–brain barrier | 14 | 26 | 92 |
Dissimilarity | |||
Mutagenicity | 11 | 8 | 7 |
Anticancer activity | 8 | 24 | 8 |
Blood–brain barrier | 7 | 8 | 52 |
Promoters of Carcinogenicity Increase | Male Rats, MR | Total MR | Female Rats, FR | Total FR | ||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Split 1 | Split 2 | Split 3 | Split 1 | Split 2 | Split 3 | |||||||||||||||
1 | 2 | 3 | 1 | 2 | 3 | 1 | 2 | 3 | 1 | 2 | 3 | 1 | 2 | 3 | 1 | 2 | 3 | |||
Molecular features extracted from SMILES | ||||||||||||||||||||
1...(....... | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 1 | 1 | 0 | 1 | 1 | 0 | 1 | 7 |
2...(....... | 1 | 1 | 1 | 0 | 0 | 0 | 1 | 1 | 1 | 6 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
2...1....... | 1 | 1 | 0 | 0 | 0 | 1 | 1 | 1 | 0 | 5 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
C...1....... | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 |
C...2....... | 0 | 1 | 0 | 1 | 1 | 0 | 0 | 1 | 0 | 4 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
N...=....... | 1 | 0 | 0 | 0 | 1 | 1 | 1 | 0 | 0 | 4 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
N...1....... | 0 | 0 | 0 | 1 | 1 | 1 | 0 | 0 | 0 | 3 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
HALO00000000 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 9 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
BOND00000000 | 1 | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 1 | 4 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 9 |
BOND10000000 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 1 | 1 | 1 | 0 | 0 | 0 | 5 |
BOND10100000 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 9 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Molecular features (invariants) extracted from molecular graph* | ||||||||||||||||||||
C5......0... | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 2 | 1 | 0 | 0 | 1 | 1 | 1 | 0 | 0 | 0 | 4 |
C6......0... | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 9 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 0 | 8 |
NNC-C...101. | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 9 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 2 |
NNC-C...110. | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 1 | 1 | 0 | 1 | 5 |
NNC-C...211. | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 9 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 9 |
NNC-C...303. | 1 | 1 | 1 | 1 | 0 | 0 | 1 | 1 | 1 | 7 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
NNC-C...321 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 0 | 7 |
NNC-O...101 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 2 |
Summation | 63 | 50 |
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Toropov, A.A.; Toropova, A.P. QSPR/QSAR: State-of-Art, Weirdness, the Future. Molecules 2020, 25, 1292. https://doi.org/10.3390/molecules25061292
Toropov AA, Toropova AP. QSPR/QSAR: State-of-Art, Weirdness, the Future. Molecules. 2020; 25(6):1292. https://doi.org/10.3390/molecules25061292
Chicago/Turabian StyleToropov, Andrey A., and Alla P. Toropova. 2020. "QSPR/QSAR: State-of-Art, Weirdness, the Future" Molecules 25, no. 6: 1292. https://doi.org/10.3390/molecules25061292
APA StyleToropov, A. A., & Toropova, A. P. (2020). QSPR/QSAR: State-of-Art, Weirdness, the Future. Molecules, 25(6), 1292. https://doi.org/10.3390/molecules25061292