Perceiving the Concealed and Unreported Pharmacophoric Features of the 5-Hydroxytryptamine Receptor Using Balanced QSAR Analysis
Abstract
:1. Introduction
2. Results
3. Discussion
4. Materials and Methods
4.1. Selection of Dataset
4.2. Calculation of Molecular Descriptors and Objective Feature Selection (OFS)
4.3. Splitting the Dataset and Subjective Feature Selection (SFS)
4.4. Building Regression Model and Its Validation
4.5. Molecular Docking
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
SMILES | Simplified molecular-input line-entry system |
GA | Genetic algorithm |
MLR | Multiple linear regression |
QSAR | Quantitative structure−activity relationship |
WHO | World Health Organization |
ADMET | Absorption, distribution, metabolism, excretion, and toxicity |
OLS | Ordinary least square |
QSARINS | QSAR Insubria |
OECD | Organisation for Economic Co-operation and Development |
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Molecular Descriptor | Description | Software Used for Calculation | Correlation with pKi |
---|---|---|---|
com_Hhyd_3A | Total number of hydrogen atoms with partial charge in the range of ±0.2 within 3 Å from center of mass of molecule | PyDescriptor | −0.625 |
ringC_S_4Bc | Sum of partial charges on ring carbon atoms present within four bonds from sulfur atom | PyDescriptor | −0.696 |
flipo&S_ringN3B | Frequency of occurrence of ring nitrogen atom present exactly at three bonds from lipophilic atom | PyDescriptor | −0.248 |
sp3N_sp2O_8B | Total number of sp3-hybridized nitrogen atoms present within eight bonds from sp2-hybridized oxygen atoms | PyDescriptor | −0.133 |
KRFPC620 | Nitrogen attached to three CH3CH2- groups | PaDEL | −0.444 |
fsp3Cdon1B | Frequency of occurrence of H-bond donor atom bonded with sp3-hybridized carbon atom | PyDescriptor | 0.026 |
Parameter | Value | Parameter | Value |
---|---|---|---|
R2tr | 0.783 | Q2LMO | 0.779 |
R2adj. | 0.781 | R2Yscr | 0.006 |
RMSEtr | 0.419 | RMSEex | 0.425 |
MAEtr | 0.350 | MAEex | 0.357 |
CCCtr | 0.878 | R2ex | 0.772 |
R2cv (Q2loo) | 0.780 | Q2-F1 | 0.768 |
RMSEcv | 0.422 | Q2-F2 | 0.768 |
MAEcv | 0.352 | Q2-F3 | 0.777 |
CCCcv | 0.876 | CCCex | 0.871 |
Molecule Number | SMILES | Ki (nM) | Affinity- Docking Score (Kcal/mol) |
---|---|---|---|
741 | CC(=O)Nc(cc1)ccc1CCNICC2Cc(c23)ccc4c3ccn4S(=O)(=O)c5ccccc5 | 79.43 | −12.2 |
134 | C1NCCCC1C(=O)Nc(ccc2)c(c23)[nH]nc3S(=O)(=O)c4cccc(c45)cccc5 | 9.8 | −12 |
489 | c1cccc(c12)[nH]cc2C(C3=O)CC(=O)N3CCCN(CC4)CCC4c5c[nH]c(c56)ccc(c6)OC | 264 | −11.9 |
490 | c1cccc(c12)[nH]cc2C(C3=O)CC(=O)N3CCN(CC4)CCC4c5c[nH]c(c56)ccc(F)c6 | 1146 | −11.8 |
1093 | CC(=O)Nc(n1)[nH]c(c1C)-c2cn(c(c23)cccc3)S(=O)(=O)c4cccc(c45)cccc5 | 13 | −11.7 |
668 | CI(C)CCC1c2c[nH]c(c23)ccc(c3)NS(=O)(=O)c(ccc4)c(c45)nccc5 | 21.2 | −11.7 |
133 | C1CCCCN1CCC(=O)Nc(ccc2)c(c23)[nH]nc3S(=O)(=O)c4cccc(c45)cccc5 | 24 | −11.7 |
381 | FC(F)(F)c1cc(ccc1)S(=O)(=O)n(c(c2c34)CCC(C2)N)c3ccc(c4)OC | 39.1 | −11.7 |
805 | c1cccc(c12)ccc(c2)S(=O)(=O)NCCN(CC3)CC=C3c4c[nH]c(c45)ccc(F)c5 | 67 | −11.7 |
628 | c1cccc(c12)CN([C@@H](C2)C(=O)N)C(=O)CCCCN3CCN(CC3)c(cccc4)c4-c5ccccc5 | 594 | −11.7 |
1086 | CCn1cncc1-c2c[nH]c(c23)ccc(Br)c3 | 1349 | −7.3 |
1016 | CCn1cncc1-c2c[nH]c(c23)cccc3 | 3020 | −7.3 |
1203 | N1CCC[C@@H]1Cc2c[nH]c(c23)cccc3 | 60 | −7.2 |
1202 | c1cccc(c12)n(cc2)C[C@H]3CCCN3C | 550 | −7.2 |
339 | NCCc1cc(ccc1)Sc2ccccc2 | 115 | −7.1 |
93 | CCN(CC)CCc1c[nH]c(c12)cccc2 | 575 | −6.4 |
738 | NCCc1c[nH]c(c12)ccc(c2)O | 42.333 | −6.2 |
534 | CC(N)Cc1c[nH]c(c12)cccc2 | 910.505 | −6.2 |
444 | NCCc1c[nH]c(c12)ccnc2 | 64 | −5.7 |
445 | CN(C)CCc1c[nH]c(c12)ccnc2 | 100 | −5.7 |
Molecule Number | SMILES (Simplified Molecular Input Line Entry System) Notation | Ki(nM) | pKi(M) | Docking Score (Kcal/mol) |
---|---|---|---|---|
681 | C1CNCCN1c(ccc2)c(c23)scc3S(=O)(=O)c4ccccc4 | 0.5006 | 9.301 | −9 |
271 | Cc(n1)cc(NC)n(c12)nc(NC)c2S(=O)(=O)c3ccccc3 | 0.5754 | 9.24 | −8.3 |
142 | C1CNCCC1Nc(c2)ccc(c23)[nH]nc3S(=O)(=O)c(c4)ccc(c45)cccc5 | 0.6 | 9.222 | −10.8 |
279 | Cc(n1)IN)c(C)n(c12)nc(NC)c2S(=O)(=O)c3ccccc3 | 0.6457 | 9.19 | −8.4 |
428 | CN(C1)CIn2)c1c(C)n(c23)nc(NC)c3S(=O)(=O)c4ccccc4 | 0.66 | 9.18 | −9.1 |
622 | O=I(C)c(=O)n(C)c(c12)ncn2CCCCN3CCN(CC3)c4ccccc4 | 14210 | 4.847 | −9.6 |
543 | c1cccc(OC)c1N(CC2)CCICCCCI(=O)N(C)C(=O)C3(C)c4ccccc4 | 14650 | 4.834 | −10.1 |
267 | c1ccccc1N(CICCN2CC(O)CN3C(=O)N(C)C(=O)C3(c4ccccc4)c5ccccc5 | 20410 | 4.69 | −9.7 |
542 | c1cccc(F)cICC2)I2CCCCCN3C(=O)N(C)C(=O)C3(C)c4ccccc4 | 25520 | 4.593 | −10.1 |
266 | c1cI(OC)c1N(CC2)CCN2CCCN3C(=O)N(C)C(=O)C3(c4ccccc4)c5ccccc5 | 29070 | 4.537 | −10.8 |
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Bukhari, S.N.A.; Elsherif, M.A.; Junaid, K.; Ejaz, H.; Alam, P.; Samad, A.; Jawarkar, R.D.; Masand, V.H. Perceiving the Concealed and Unreported Pharmacophoric Features of the 5-Hydroxytryptamine Receptor Using Balanced QSAR Analysis. Pharmaceuticals 2022, 15, 834. https://doi.org/10.3390/ph15070834
Bukhari SNA, Elsherif MA, Junaid K, Ejaz H, Alam P, Samad A, Jawarkar RD, Masand VH. Perceiving the Concealed and Unreported Pharmacophoric Features of the 5-Hydroxytryptamine Receptor Using Balanced QSAR Analysis. Pharmaceuticals. 2022; 15(7):834. https://doi.org/10.3390/ph15070834
Chicago/Turabian StyleBukhari, Syed Nasir Abbas, Mervat Abdelaziz Elsherif, Kashaf Junaid, Hasan Ejaz, Pravej Alam, Abdul Samad, Rahul D. Jawarkar, and Vijay H. Masand. 2022. "Perceiving the Concealed and Unreported Pharmacophoric Features of the 5-Hydroxytryptamine Receptor Using Balanced QSAR Analysis" Pharmaceuticals 15, no. 7: 834. https://doi.org/10.3390/ph15070834