Pharmacophore-Based Study: An In Silico Perspective for the Identification of Potential New Delhi Metallo-β-lactamase-1 (NDM-1) Inhibitors
Abstract
:1. Introduction
2. Results and Discussion
2.1. Protein Structure and Docking
2.2. Pharmacophore
2.3. Virtual Screening
2.4. Tanimoto and Clustering
2.5. Interaction Analysis
2.6. ADMET Properties
2.7. Molecular Dynamics Simulation (300 ns)
2.8. Principal Component Analysis
2.9. Free Energy Landscape
2.10. Binding Free Energies
3. Material and Methods
3.1. Protein Structure and Molecular Docking
3.2. Pharmacophore
3.3. Virtual Screening
3.4. Tanimoto Similarity and Clustering
3.5. ADMET Properties
3.6. Molecular Dynamics Simulation
3.7. PCA and FEL
3.8. MM/GBSA
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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S.no | Top BS (kcal/mol) | Compound ID | Normalized BS | S.no | Top BS (kcal/mol) | Compound ID | Normalized BS |
---|---|---|---|---|---|---|---|
1 | −8.884 | ZINC14802618 | −7.86967 | 35 | −7.131 | ZINC29142850 | −6.72855 |
2 | −8.104 | ZINC94303138 | −7.79811 | 36 | −7.305 | ZINC14265783 | −6.72711 |
3 | −8.696 | ZINC71983666 | −7.71111 | 37 | −6.965 | ZINC72008621 | −6.70222 |
4 | −8.296 | ZINC02927577 | −7.53545 | 38 | −7.233 | ZINC11748858 | −6.69533 |
5 | −8.45 | ZINC71986759 | −7.50078 | 39 | −7.442 | ZINC04851607 | −6.69456 |
6 | −8.168 | ZINC71924775 | −7.43711 | 40 | −6.921 | ZINC40034395 | −6.63233 |
7 | −7.715 | ZINC71924780 | −7.40022 | 41 | −6.824 | ZINC78498764 | −6.62466 |
8 | −8.327 | ZINC02927521 | −7.39134 | 42 | −7.307 | control_hydrolyzed-oxacillin | −6.59467 |
9 | −7.827 | ZINC35548858 | −7.29667 | 43 | −6.939 | ZINC12384097 | −6.56033 |
10 | −7.927 | ZINC78607001 | −7.23967 | 44 | −7.142 | ZINC04851208 | −6.52722 |
11 | −7.496 | ZINC32932272 | −7.21522 | 45 | −6.751 | ZINC39357686 | −6.52045 |
12 | −8.214 | ZINC32932744 | −7.19656 | 46 | −7.175 | ZINC40868984 | −6.51555 |
13 | −7.915 | ZINC40133417 | −7.18156 | 47 | −6.987 | ZINC12741918 | −6.50422 |
14 | −7.529 | ZINC11418769 | −7.15845 | 48 | −6.894 | ZINC58344565 | −6.45766 |
15 | −7.749 | ZINC38697967 | −7.12411 | 49 | −7.243 | ZINC04851257 | −6.45056 |
16 | −7.591 | ZINC05441336 | −7.11533 | 50 | −6.844 | ZINC39357685 | −6.43023 |
17 | −7.578 | ZINC05006123 | −7.03278 | 51 | −6.813 | ZINC32764688 | −6.42144 |
18 | −7.66 | ZINC65610187 | −7.03189 | 52 | −7.085 | ZINC78444367 | −6.41122 |
19 | −7.414 | ZINC57076878 | −7.03111 | 53 | −6.945 | ZINC13012826 | −6.40767 |
20 | −7.499 | ZINC24929111 | −7.016 | 54 | −6.649 | ZINC14481796 | −6.32767 |
21 | −7.591 | ZINC78899383 | −7.00111 | 55 | −7.135 | ZINC78556987 | −6.32434 |
22 | −7.381 | ZINC12753875 | −6.95856 | 56 | −6.918 | ZINC05393487 | −6.29611 |
23 | −7.495 | ZINC12360899 | −6.95567 | 57 | −7.049 | ZINC04851606 | −6.29289 |
24 | −7.378 | ZINC11486594 | −6.93356 | 58 | −6.935 | ZINC09743679 | −6.28045 |
25 | −7.708 | ZINC78717525 | −6.91089 | 59 | −6.642 | ZINC38698169 | −6.25534 |
26 | −7.488 | ZINC65610185 | −6.90978 | 60 | −6.914 | ZINC09743666 | −6.24689 |
27 | −7.4 | ZINC14519389 | −6.88178 | 61 | −6.907 | ZINC16818978 | −6.23034 |
28 | −7.156 | ZINC11486626 | −6.84944 | 62 | −7.147 | ZINC02333181 | −6.17489 |
29 | −7.123 | ZINC71881695 | −6.77878 | 63 | −6.804 | ZINC19526877 | −6.11789 |
30 | −7.115 | ZINC48302108 | −6.77722 | 64 | −6.42 | ZINC14500916 | −6.03978 |
31 | −7.605 | ZINC06606192 | −6.765 | 65 | −6.601 | ZINC15419422 | −5.98367 |
32 | −7.146 | ZINC31954796 | −6.75566 | 66 | −6.813 | ZINC06606196 | −5.88189 |
33 | −7.155 | ZINC04851213 | −6.74545 | 67 | −6.292 | ZINC05253733 | −5.68456 |
34 | −7.097 | ZINC01028321 | −6.736 |
Compounds | Conventional Hydrogen Bonds | Carbon-Hydrogen Bonds | Pi-Cation | Pi-Alkyl | Pi-Pi T-Shaped Interaction | Pi-Sigma Bonds |
---|---|---|---|---|---|---|
Control | Gln123, His250, Lys211, Asn220, Asp124, His189 | His122, Gly219, | Trp93 | |||
Z1 | His 189 | His122, Gly219, Asp124 | Met67, Met154 | Ile35, His250 | Trp96 | |
Z2 | Asn220 | Met67 | His122, Val73 | Phe70 | Ile35 | |
Z3 | Gly219, Ser217, His250, Lys211, Lys216, Asp212, Ala74 | His189, Val73 | Met67, Phe70 |
Molecule | ZINC29142850 (ZN1) | ZINC78607001 (ZN2) | ZINC94303138 (ZN3) |
---|---|---|---|
MW | 458.53 | 423.94 | 839.94 |
Rotatable bonds | 10 | 7 | 28 |
H-bond acceptors | 5 | 2 | 14 |
H-bond donors | 2 | 1 | 6 |
MR | 125.96 | 125.94 | 203.12 |
TPSA | 128.45 | 54.34 | 300.4 |
iLOGP | 1.49 | 3.69 | 0 |
ESOL class | Soluble | Moderately soluble | Moderately soluble |
Lipinski violations | 0 | 0 | 3 |
PAINS alerts | 0 | 0 | 1 |
Predicted toxicity class | 4 | 4 | 4 |
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Alkhatabi, H.A.; Alatyb, H.N. Pharmacophore-Based Study: An In Silico Perspective for the Identification of Potential New Delhi Metallo-β-lactamase-1 (NDM-1) Inhibitors. Pharmaceuticals 2024, 17, 1183. https://doi.org/10.3390/ph17091183
Alkhatabi HA, Alatyb HN. Pharmacophore-Based Study: An In Silico Perspective for the Identification of Potential New Delhi Metallo-β-lactamase-1 (NDM-1) Inhibitors. Pharmaceuticals. 2024; 17(9):1183. https://doi.org/10.3390/ph17091183
Chicago/Turabian StyleAlkhatabi, Heba Ahmed, and Hisham N. Alatyb. 2024. "Pharmacophore-Based Study: An In Silico Perspective for the Identification of Potential New Delhi Metallo-β-lactamase-1 (NDM-1) Inhibitors" Pharmaceuticals 17, no. 9: 1183. https://doi.org/10.3390/ph17091183
APA StyleAlkhatabi, H. A., & Alatyb, H. N. (2024). Pharmacophore-Based Study: An In Silico Perspective for the Identification of Potential New Delhi Metallo-β-lactamase-1 (NDM-1) Inhibitors. Pharmaceuticals, 17(9), 1183. https://doi.org/10.3390/ph17091183