Inferring Therapeutic Targets in Candida albicans and Possible Inhibition through Natural Products: A Binding and Physiological Based Pharmacokinetics Snapshot
Abstract
:1. Introduction
2. Material & Methods
2.1. Data Retrieval
2.2. Essentiality Analysis
2.3. Drug Target Mining
2.4. Virtual Screening
2.5. ADMET Profiling
3. Results
3.1. Therapeutic Candidate Mining
3.2. Virtual Screening
3.3. ADMET Profiling
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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S. No. | Protein Accession Number | Protein Name | Protein Length | DrugBank Alignment Length | E-Value | Subcellular Localization |
---|---|---|---|---|---|---|
1 | XP_019330652.1 | lumazine synthase | 206 | 157 | 1.33396 × 10−29 | Cytoplasmic |
2 | XP_019330750.1 | 3-deoxy−7-phosphoheptulonate synthase | 371 | 356 | 5.95566 × 10−127 | Cytoplasmic |
3 | XP_019330821.1 | trehalose 6-phosphate synthase/phosphatase complex subunit | 1007 | 383 | 1.09471 × 10−38 | Nuclear/Plasma membrane |
4 | XP_019331058.1 | anthranilate synthase | 522 | 410 | 3.47489 × 10−58 | Cytoplasmic |
5 | XP_019331115.1 | Bgl22p | 924 | 358 | 1.55548 × 10−12 | Cytoplasmic |
6 | XP_710092.2 | 4-amino-4-deoxychorismate synthase | 822 | 461 | 1.1003 × 10−36 | Nuclear |
7 | XP_710211.2 | bifunctional chorismate synthase/riboflavin reductase [NAD(P)H] | 413 | 376 | 1.39864 × 10−52 | Mitochondrial/Nuclear |
8 | XP_710312.1 | tryptophan synthase | 702 | 394 | 1.85163 × 10−144 | Cytoplasmic |
9 | XP_710700.2 | pantoate--beta-alanine ligase | 316 | 305 | 1.03048 × 10−68 | Nuclear |
10 | XP_710729.1 | 3-deoxy−7-phosphoheptulonate synthase | 370 | 353 | 3.03778 × 10−117 | Cytoplasmic/Nuclear |
11 | XP_711703.1 | hypothetical protein CAALFM_CR05750WA | 342 | 129 | 5.37008 × 10−0.8 | Cytoplasmic |
12 | XP_711706.1 | alpha, alpha-trehalose-phosphate synthase (UDP-forming) TPS1 | 478 | 472 | 3.18455 × 10−92 | Cytoplasmic |
13 | XP_712232.1 | isocitrate lyase 1 | 550 | 250 | 2.64563 × 10−44 | Peroxisomal |
14 | XP_713033.1 | sulfonate dioxygenase | 386 | 289 | 1.79648 × 10−24 | Nuclear/Cytoplasmic |
15 | XP_713320.2 | trifunctional histidinol dehydrogenase/phosphoribosyl-AMP cyclohydrolase/phosphoribosyl-ATP diphosphatase | 838 | 424 | 9.87896 × 10−114 | Cytoplasmic |
16 | XP_713806.1 | hypothetical protein CAALFM_C111290WA | 369 | 261 | 4.84039 × 10−35 | Cytoplasmic |
17 | XP_714207.2 | trifunctional dihydropteroate synthetase/dihydrohydroxymethylpterin pyrophosphokinase/dihydroneopterin aldolase | 829 | 788 | 3.71427 × 10−161 | Nuclear/Cytoplasmic |
18 | XP_714543.2 | hypothetical protein CAALFM_C209810CA | 434 | 400 | 1.30711 × 10−42 | Cytoplasmic |
19 | XP_714705.1 | hypothetical protein CAALFM_C305640WA | 425 | 308 | 2.28143 × 10−35 | Cytoplasmic |
20 | XP_714872.2 | Dqd1p | 146 | 124 | 4.79446 × 10−33 | Cytoplasmic |
21 | XP_715352.2 | uroporphyrinogen-III C-methyltransferase | 561 | 418 | 2.52115 × 10−42 | Nuclear/Cytoplasmic |
22 | XP_715357.1 | Ebp7p | 392 | 385 | 3.40361 × 10−70 | Cytoplasmic |
23 | XP_715408.1 | anthranilate phosphoribosyltransferase | 369 | 313 | 2.82806 × 10−41 | Cytoplasmic |
24 | XP_715440.2 | Oye32p | 432 | 379 | 4.31391 × 10−35 | Cytoplasmic |
25 | XP_715739.1 | dihydroorotase | 358 | 356 | 4.16856 × 10−54 | Cytoplasmic |
26 | XP_716238.1 | hypothetical protein CAALFM_CR08310CA | 385 | 286 | 2.24051 × 10−36 | Nuclear |
27 | XP_716751.1 | Hypothetical protein CAALFM_C601400WA | 676 | 419 | 5.7776 × 10−14 | Plasma membrane |
28 | XP_717003.2 | Nik1p | 1081 | 227 | 7.42174 × 10−20 | Nuclear/Cytoplasmic |
29 | XP_718052.2 | Ymx6p | 622 | 304 | 4.11558 × 10−0.6 | Plasma membrane |
30 | XP_718069.2 | phenylacrylic acid decarboxylase | 229 | 185 | 7.40789 × 10−68 | Plasma membrane |
31 | XP_718219.1 | 5-methyltetrahydropteroyltriglutamate-homocysteine S-methyltransferase | 775 | 767 | 0 | Cytoplasmic |
32 | XP_718255.2 | dethiobiotin synthase | 212 | 205 | 7.64158 × 10−16 | Chloroplast/cytoplasmic |
33 | XP_718258.2 | biotin synthase | 374 | 323 | 1.05435 × 10−100 | Mitochondrial |
34 | XP_719019.1 | 3-methyl-2-oxobutanoate hydroxymethyltransferase | 309 | 262 | 1.03531 × 10−55 | Mitochondrial |
35 | XP_719048.1 | 2-isopropylmalate synthase | 579 | 603 | 5.36732 × 10−170 | Cytoplasmic |
36 | XP_719116.2 | L-methionine (R)-S-oxide reductase | 175 | 134 | 2.56642 × 10−30 | Cytoplasmic |
37 | XP_721010.2 | trifunctional hydroxymethylpyrimidine kinase/phosphomethylpyrimidine kinase/thiaminase | 548 | 273 | 2.42294 × 10−26 | Cytoplasmic |
38 | XP_721446.1 | pyridoxine biosynthesis protein | 292 | 285 | 9.51495 × 10−106 | Cytoplasmic |
39 | XP_721536.1 | trehalose-phosphatase | 888 | 385 | 1.08126 × 10−54 | Cytoplasmic |
40 | XP_721716.2 | hypothetical protein CAALFM_C302070CA | 388 | 287 | 5.53839 × 10−34 | Cytoplasmic |
41 | XP_721934.1 | ATP phosphoribosyltransferase | 298 | 298 | 3.46987 × 10−33 | Cytoplasmic |
42 | XP_721932.2 | riboflavin synthase | 237 | 219 | 5.41917 × 10−35 | Cytoplasmic |
43 | XP_722690.1 | fructose-bisphosphate aldolase | 359 | 343 | 2.15136 × 10−129 | Cytoplasmic |
44 | XP_722769.2 | Aro1p | 1551 | 430 | 2.38324 × 10−70 | Cytoplasmic |
45 | XP_723161.2 | trifunctional fatty acid synthase sub-unit | 1884 | 763 | 2.04704 × 10−107 | Cytoplasmic |
46 | XP_723517.1 | Mts1p | 513 | 290 | 3.95336 × 10−26 | Plasma membrane |
Molecular Formula | Ligand Atom and Its Position | Receptor Atom/Residue | Interaction Type | Distance (Å) | Energy (Kcal/mol) | MM/PBSA Value of Complex | MM/PBSA Value of Ligand | |
---|---|---|---|---|---|---|---|---|
Control | C13H10N4O | N29 | OD1/ASP291 | ionic | 2.92 | −5.0 | −25.68 | 0.24 |
ZINC13507461 | C21H39O7P | O57 | OD2/ASP289 | H-donor | 3.25 | −1.7 | −25.50 | −0.26 |
O65 | OE2/GLU182 | H-donor | 2.99 | −5.3 | ||||
O67 | OE1/GLU182 | H-donor | 2.87 | −7.1 | ||||
O64 | N/THR290 | H-acceptor | 3.61 | −0.7 | ||||
(4-Hydroxybenzyl)thiocarbamic acid | C8H9NO2S | O14 | O ASN287 | H-donor | 2.88 | −0.7 | −25.57 | −0.03 |
O12 | N/SER268 | H-acceptor | 2.97 | −2.2 | ||||
O12 | OG/SER268 | H-acceptor | 3.11 | −0.6 | ||||
O14 | N/GLY266 | H-acceptor | 2.97 | −0.9 | ||||
6-ring | CA/GLU182 | pi-H | 3.92 | −0.7 | ||||
6-ring | N/ASP183 | pi-H | 4.61 | −0.9 | ||||
Chelerythrine | C21H18NO4+ | C8 | O/ASN233 | H-donor | 3.38 | −0.6 | −25.64 | 0.11 |
Property | Model Name | Unit | Predicted Value for Control | Predicted Value for ZINC13507461 | Predicted Value for (4-Hydroxybenzyl)thiocarbamic Acid | Predicted Value for Chelerythrine |
---|---|---|---|---|---|---|
Absorption | Water solubility | Numeric (log mol/L) | −3.655 | −4.445 | −2.833 | −3.123 |
Caco2 permeability | Numeric (log Papp in 10−6 cm/s) | 0.222 | 0.521 | 0.41 | 1.429 | |
Intestinal absorption (human) | Numeric (% absorbed) | 86.122 | 59.414 | 57.252 | 96.43 | |
Skin permeability | Numeric (log Kp) | −2.766 | −2.702 | −3.041 | −2.946 | |
P-glycoprotein substrate | Categorical (Yes/No) | Yes | Yes | Yes | No | |
P-glycoprotein I inhibitor | Categorical (Yes/No) | No | Yes | No | Yes | |
P-glycoprotein II inhibitor | Categorical (Yes/No) | No | Yes | No | Yes | |
Distribution | VDss (human) | Numeric (log L/kg) | 0.531 | −0.866 | −0.716 | 0.53 |
Fraction unbound (human) | Numeric (Fu) | 0.188 | 0.151 | 0.3 | 0.311 | |
BBB permeability | Numeric (log BB) | −0.513 | −1.571 | −1.302 | 0.025 | |
CNS permeability | Numeric (log PS) | −2.332 | −3.099 | −4.217 | −2.16 | |
Metabolism | CYP3A4 substrate | Categorical (Yes/No) | No | Yes | No | Yes |
CYP1A2 inhibitor | Categorical (Yes/No) | Yes | No | No | No | |
CYP2C19 inhibitor | Categorical (Yes/No) | Yes | No | No | Yes | |
CYP2D6 inhibitor | Categorical (Yes/No) | No | No | No | Yes | |
Excretion | Total clearance | Numeric (log ml/min/kg) | 0.354 | 0.453 | 0.154 | 0.879 |
Toxicity | Max. tolerated dose (human) | Numeric (log mg/kg/day) | 0.071 | 0.079 | 0.848 | 0.095 |
Oral rat acute toxicity (LD50) | Numeric (mol/kg) | 2.513 | 2.985 | 3.023 | 3.411 | |
Oral rat chronic toxicity (LOAEL) | Numeric (log mg/kg_bw/day) | 2.178 | 2.733 | 2.966 | 1.692 | |
T. Pyriformis toxicity | Numeric (log ug/L) | 0.598 | 0.292 | 0.271 | 0.333 | |
Minnow toxicity | Numeric (log mM) | 1.733 | −1.682 | 3.117 | 0.78 |
Condition | Compounds | Intestinal Absorption of Compound Fa (%) | Portal Vein Absorption of Compound FDp (%) | Bioavailable Drug F (%) | Cmax (µg/mL) | Tmax (h) | AUC(0-inf) (ng-h/mL) | AUC(0-t) (ng-h/mL) |
---|---|---|---|---|---|---|---|---|
Healthy | Control | 81.626 | 80.078 | 25.145 | 3.3904 | 9.7593 | 1,034,000 | 27,820 |
ZINC13507461 | 11.461 | 10.906 | 3.6584 | 0.4671 | 10 | 2622.2 | 2622.2 | |
Chelerythrine | 99.582 | 99.42 | 31.551 | 4.3333 | 2.5876 | 226,700 | 38,260 | |
(4-Hydroxybenzyl)thiocarbamic acid | 79.27 | 77.024 | 24.757 | 2.9855 | 8.8793 | 431,900 | 23,550 | |
Cirrhosis | Control | 82.783 | 80.784 | 80.784 | 5.6819 | 9.8013 | 4,499,000 | 47,250 |
ZINC13507461 | 11.565 | 11.025 | 11.025 | 1.0741 | 10 | 5728 | 5728 | |
Chelerythrine | 99.903 | 99.866 | 99.866 | 0.8644 | 0.865 | 26,090,000 | 5852.2 | |
(4-Hydroxybenzyl)thiocarbamic acid | 78.662 | 76.185 | 76.185 | 2.2192 | 9.9329 | 16,710 | 16,710 | |
Renal impairment | Control | 82.792 | 80.896 | 80.896 | 4.9496 | 9.916 | 1,215,000 | 40,110 |
ZINC13507461 | 11.694 | 11.148 | 11.148 | 1.0993 | 10 | 5819.1 | 5819.1 | |
Chelerythrine | 99.645 | 99.487 | 31.45 | 4.2081 | 2.6187 | 225,600 | 37,180 | |
(4-Hydroxybenzyl)thiocarbamic acid | 79.022 | 76.616 | 25.489 | 3.1081 | 8.8371 | 839,000 | 24,430 |
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Basharat, Z.; Khan, K.; Jalal, K.; Alnasser, S.M.; Majeed, S.; Zehra, M. Inferring Therapeutic Targets in Candida albicans and Possible Inhibition through Natural Products: A Binding and Physiological Based Pharmacokinetics Snapshot. Life 2022, 12, 1743. https://doi.org/10.3390/life12111743
Basharat Z, Khan K, Jalal K, Alnasser SM, Majeed S, Zehra M. Inferring Therapeutic Targets in Candida albicans and Possible Inhibition through Natural Products: A Binding and Physiological Based Pharmacokinetics Snapshot. Life. 2022; 12(11):1743. https://doi.org/10.3390/life12111743
Chicago/Turabian StyleBasharat, Zarrin, Kanwal Khan, Khurshid Jalal, Sulaiman Mohammed Alnasser, Sania Majeed, and Marium Zehra. 2022. "Inferring Therapeutic Targets in Candida albicans and Possible Inhibition through Natural Products: A Binding and Physiological Based Pharmacokinetics Snapshot" Life 12, no. 11: 1743. https://doi.org/10.3390/life12111743