In-Silico Investigation and ADMET Prediction of Potential Antihyperpigmentation Phytochemicals against Tyrosinase Inhibitors
Shital S. Dange1, Pooja M. Chopade1, Pranali R. Mane1, Snehal A. Kakde1, Pratiksha Y. Parit1, Vaishnavi G. Latthe1, Shalini A. Shinde1*, Akash R. Thombre2*, Dhanraj R. Jadge1
1Womens College of Pharmacy, Peth-Vadgaon 416112, India.
2Ashokrao Mane Institute of Pharmacy, Ambap 416112, India.
*Corresponding Author E-mail: ms.shalinishinde177@gmail.com
ABSTRACT:
Hyperpigmentation refers to skin conditions involving discoloration, darkening, and changes in pigmentation, including melasma, post-inflammatory hyperpigmentation, ephelides, and lentigines. Melasma, a common acquired hypermelanosis, causes irregular light to dark brown or gray-brown patches on sun-exposed skin and affects around 80% of Indian women. It occurs due to excessive melanin production, which is made through melanogenesis. When melanin builds up in epithelial cells, it’s called melanosis. Epidermal melanosis occurs with normal melanocyte numbers but excess melanin in the upper skin layer. In contrast, dermal melanosis involves melanin in the dermis, between collagen bundles. A molecular docking and ADMET study was conducted using the human tyrosinase protein and 50 phytochemicals that have the potential for antihyperpigmentation in drug discovery. The protein structure was obtained and processed with Biovia Discovery Studio, while phytochemical structures were generated using Open Babel and VConf from NCBI PubChem. Docking was done with PyRx and AutodockVina, and ADMET properties were analyzed using SwissADME and pkCMS. 18-Beta Glycyrrhetinic acid showed the highest binding affinity, with potential anti-hyperpigmentation activity, low toxicity, and good tissue absorption, suggesting it could be a promising candidate for further in vitro studies and antihyperpigmentation drug development.
KEYWORDS: Antihyperpigmentation, Molecular Docking, ADMET 7rk7, Tyrosinase enzyme, Drug likeness properties.
Facial hyperpigmentation is a general term that refers to an increased concentration of melanin in the epidermis, dermis, or both.1 This condition can result from various factors and may present as a localized issue or as part of a broader, systemic disorder. Hyperpigmentation can be acquired, congenital, or inherited.2
Melasma, derived from the Greek word melas, meaning "black," is also known as chloasma or the "mask of pregnancy." It is characterized by irregular hypermelanosis of the face and neck, appearing as light to dark brown patches, occasionally with an ashen gray-brown hue. While melasma is the most prevalent cause of facial pigmentation, other types include ashy dermatosis, Riehl’s melanosis, poikiloderma of Civatte, erythrosis peribuccale of Brock, as well as drug-induced and post-inflammatory hyperpigmentation.3
Human skin tones range from dark brown to nearly colorless, with some shades appearing reddish due to the blood beneath the skin. The primary factor determining skin color is the type and amount of melanin, the pigment responsible for coloration. Skin color variation is predominantly genetic.4 Many societies attach social value to skin color differences, often linking them to historical political and economic divisions. In countries like India, individuals with certain skin discolorations may face social isolation, partly due to associations with diseases like leprosy.5
Skin tone differences are among the most noticeable traits in human populations, historically influencing racial classification through color terminology. For practical purposes, such as determining sun exposure time for tanning, Fitzpatrick’s classification identifies six skin types, arranged from lightest to darkest.6
Melanin production is a complex process involved in inflammation, sun protection, and other biological functions. Melanocytes, in collaboration with the enzyme tyrosinase, produce and convert dopa into melanin. This pigment is stored in melanosomes, which are absorbed by keratinocytes and eventually shed along with the outer skin layer (stratum corneum). Factors influencing melanin production and skin color include not only keratinocytes but also Langerhans cells, mast cells, and potentially lymphocytes.7
Effective treatment of pigment disorders focuses on modulating melanin production while addressing other underlying skin conditions. Hyperpigmentation treatments aim to accelerate epidermal turnover to remove surface pigment (using glycolic acid, salicylic acid, and lactic acid), enhance melanosome transfer, and suppress tyrosinase activity (with tretinoin). Other approaches include slowing melanocyte proliferation, reducing their secretory activity, managing inflammation (using corticosteroids), and inhibiting tyrosinase to decrease melanin synthesis (with hydroquinone).8,9,10
MATERIALS AND METHODS:
Protein Preparation:
The previously reported 3D crystal structure of the enzyme tyrosine kinase for hyperpigmentation with PDB Id 7RK7, having resolution 1.98, was downloaded from the online RCSB protein data bank (https://www.rcsb.org/). The downloaded protein structure was cleaned by removing all the water molecules and previously bound ligand groups. Further, the cleaned protein structure was protonated by adding polar hydrogen to define the amino acids' correct ionization and tautomeric states. The protein cleaning and preparation protocol was carried out using BIOVIA Discovery Studio Visualizer.
Active Site Preparation:
It was projected that the 7RK7 active site will be found in literature, Discovery Studio, and the PDB. To guarantee that the target protein binding site is covered by the grid box configuration in the PyRx software, the correct predicted amino acid residue must be chosen. After that, it was discovered that the study's resolved centre point was X: -22.8087, Y:-55.7715, Z: 0.1212 with dimensions (Angstrom) of X: 25, Y: 25, Z: 25.
Ligand Preparation:
The structures and smiles of over 50 phytoconstituents were downloaded from the IMPPAT and PubChem databases. The downloaded phytoconstituents are prepared in Discovery Studio by removing heteroatoms and adding polar hydrogen atoms and saved in PDB format. The prepared phytoconstituents were subjected to molecular docking.
Molecular Docking Simulations:
Molecular docking of prepared phytoconstituents and tyrosine kinase (PDB: 7RK7) was done to determine binding affinity and interaction between them. PyRx 0.8 was used to carry out molecular docking. The proteins and phytoconstituents structures were imported into the PyRx program. Using Opel Babel plug in of PyRx, the structure of the flavonoids was converted to PDBQT format, and further the energy minimization of all the selected structures of phytoconstituents were done and converted as AutoDock ligand files With the following dimensions: X: 45.5873616028 Å, Y: 60.0910002518 Å, Z: 58.2694099617 Å, and center X: 4.011, Y: -13.3762, Z: 3.5934, the grid box was chosen using Vina workspace to cover the binding site residues. Eight was the default setting for exhaustiveness. Concerning the chosen target protein (PDB: 4XG6), nine distinct conformations were anticipated for every ligand structure. Each ligand's optimal posture with the lowest binding affinity was chosen. We used BIOVIA Discovery Studio 2020 to display and evaluate docking interactions.
Theoretical Prediction of ADMET Parameters:
The top-ranked compounds were exported in SMILES format from the docking simulation to SwissADME and the pkCMS web server for toxicity and bioavailability prediction techniques like Lipinski's rule of 5. SwissADME and pkCMS are free online tools for predicting the pharmacokinetics, drug-likeness, and medicinal chemistry friendliness of small compounds (http://biosig.unimelb.edu.au/pkcsm/prediction) (Daina et al., 2017; Pires et al., 2015). The importance and typical range of the ADMET parameters chosen for this investigation.
RESULT AND DISCUSSION:
Molecular Docking Simulation:
To find novel Tyrosinase inhibitors from natural sources, molecular docking experiments were conducted. The outcome suggests that some naturally occurring substances have higher binding energies than the common medications. The table below lists the binding energies and interacting residues of the 50 compounds with common antihyperpigmentation medications. The investigation demonstrated the 3D and 2D structures of 18-beta Glycyrrhetinic acid in association with the 7rk7 protein. The picture also depicts the interaction between 18 Beta Glycyrrhetinic Acid and the ATP-binding site of 7RK7. The binding activity and ligand-protein interaction of 18 Beta Glycyrrhetinic Acid, Muberrofurnon, Artonin M, Liquiritin, Kuwanon T, Kuwanon G, Kuwanon L are also better. The interactions of the first two phytochemicals having higher binding affinity are shown in Figures 1 to 5, respectively.
Table 1: Docking and Interactions of 50 Phytochemicals against Tyrosinase Inhibitors
|
Sr.No. |
Pubchem ID |
Binding Affinity (kcal/mol) |
Interacting Residue |
Type of Interaction |
|
1 |
14982 |
-10.8 |
CYSE:180, SERD:88, LEUD:87, VALD:169, SERD:177, LYSD:119, CYSD:168, PROD:47, THRE:181, LEUE:166, LEUE:199, GLNE:184, GLUE:165, TYRE:224, HISE:14 |
Van dar Waal |
|
SERD:48, VALE:164, TRPE:119, ASPE:162, PROE:183, ASPE:182, THRD:90, VALD:118 |
Conventional Hydrogen Bond |
|||
|
PROE:185, |
Carbon Hydrogen Bond |
|||
|
2 |
5281667 |
-10.3 |
SERE:91, VALE:92, THER:90, THRE:121, HISE:163, TYRE:197, SERD:48, TYRD:94, HLYE:46, LYSD:115, GLNE:184, ASPE:42 |
Van dar Waal |
|
GLNE:41, LYSD:112 |
Conventional Hydrogen Bond |
|||
|
PROE:183 |
Unfavorable Acceptor-Acceptor |
|||
|
ASPE:162 |
Pi-Anion |
|||
|
ALAD:91 |
Pi-Donor Hydrogen Bond |
|||
|
PHED:46 |
Amide-Pi Stacked |
|||
|
3 |
9959532 |
-10.2 |
LEUE:120, HISE:163, TRPE:119, PROE:161, VALE:92, ASPE:42, PROD:47, SERD:48, PHED:46, PHEE:94, GLND:45, GLNE:184, LYSE:187 |
Van dar Waal |
|
ASPE:162, GLND:49, THRE:121 |
Conventional Hydrogen Bond |
|||
|
SERE:91 |
Carbon Hydrogen Bond |
|||
|
|
Unfavorable Donor-Donor |
|||
|
PROE:43 |
Pi-Donor Hydrogen Bond |
|||
|
THRE:90 |
Pi-Sigma |
|||
|
PROE:185 |
Alkyl |
|||
|
TYRE:197 |
Pi-Alkyl |
|||
|
4 |
44258661 |
-10.0 |
LYSE:57, VALE:56, ASPE:58, GLYE:55, GLYD:103, GLNE:105, TYRE:35, ALAA:69, ARGE:34, GLNA:72, ARGA:75, SERA:71 |
Van der Waal |
|
LYSA:68 |
Pi-Cation |
|||
|
TYRE:54 |
Pi-Sigma |
|||
|
ARGA:65 |
Alkyl |
|||
|
ARGA:65 |
Pi-Alkyl |
|||
|
5. |
503737 |
-9.9 |
THRA:31, GLNA:32, LEUB:66, TYRB:27, GLUA:232, SERB:58, LYSB:59 |
Van dar Waal |
|
SERB:53, TYRA:27, ASPA:30 |
Conventional Hydrogen Bond |
|||
|
ARGA:6 |
Unfavorable Acceptor-Acceptor |
|||
|
TYRB:64 |
Pi-Donor Hydrogen Bond |
|||
|
PHEA:241 |
Pi-Pi T-Shaped |
|||
|
PROA:235 |
Pi-Alkyl |
|||
|
6 |
184877 |
-9.9 |
THRE:90, ASPE:162, HISE:163, LEUE:120, SERE:91, LYSD:115, THRD:90, PHED:46, GLND:45, GLND:49, PHEE:94, SERD:48, VALE:92, ASPE:42, GLNE:41 |
Van dar Waal |
|
GLNE:184, TYRE:197, THRE:121 |
Conventional Hydrogen Bond |
|||
|
ALAD:91 |
Carbon Hydrogen Bond |
|||
|
VALD:92, PROE:43 |
Pi-Sigma |
|||
|
TRPE:119 |
Pi-Pi Stacked |
|||
|
PROD:47 |
Alkyl |
|||
|
PROD:47 |
Pi-Alkyl |
|||
|
7 |
15231527 |
-9.8 |
ASPE:58, ARGA:65, GLYD:102, SERA:71, SERA:38, PROA:20, GLNA:43 |
Van dar Waal |
|
GLYD:103, TYRE:35, LYSA:68, ARGA:75, ARGE:34, GLUA:19 |
Conventional Hydrogen Bond |
|||
|
GLND:105, GLNA:72 |
Unfavorable Donor-Donor |
|||
|
TYRE:54 |
Pi-Pi Stacked |
|||
|
ALAA:69 |
Alkyl |
|||
|
8 |
102004551 |
-9.8 |
ASPE:60, GLND:105, GLYD:103, TYRE:35, ALAA:69, GLNA:72, SERA:71, PROA:20, SERA:38, A SPA:39, GLNA:43, GLYE:55, ASPE:58 |
Van dar Waal |
|
LYSA:68, ARGA:75 |
Conventional Hydrogen Bond |
|||
|
GLUA:19 |
Pi-Anion |
|||
|
ARGA:65, TYRE:54 |
Alkyl |
|||
|
VALE:56 |
Pi-Alkyl |
|||
|
9 |
10740797 |
-9.5 |
VALE:56, GLYE:55, ASPE:58, TYRE:54, ALAA:69, TYRE:35, ARGE:34, GLNA:72, PROA:20, PROA:20, PHEA:22, SERA38, ASPA:39, GLNA:43 |
Van der Waal |
|
SERA:71 |
Conventional Hydrogen Bond |
|||
|
GLUA:19 |
Pi-Anion |
|||
|
LYSA:68 |
Pi-Alkyl |
|||
|
10 |
5481969 |
-9.5 |
ASPE:42, GLYE:44, GLYE:46, TYRD:94, GLND:45, PHED:46, ALAD:91, LYSD:115 |
Van der Waal |
|
LYSD:112, SERD:48 |
Conventional Hydrogen Bond |
|||
|
GLNE:41 |
Carbon Hydrogen Bond |
|||
|
PROD:47 |
Pi-Donor Hydrogen Bond |
|||
|
VALD:92 |
Alkyl |
|||
|
VALD:92 |
Pi-Alkyl |
|||
|
11 |
15224382 |
-9.4 |
ASPA:238, THRA:31, GLYA:239, GLNA:32, ARGA:48, ASPB:54, TYRB:68, LEUB:66, TYRB:27, |
Van dar Waal |
|
ASPA:30, SERB:53 |
Conventional Hydrogen Bond |
|||
|
TYRA:27, TYRB:64 |
Pi-Donor Hydrogen Bond |
|||
|
PHEA:241 |
Pi-Pi T-Shaped |
|||
|
PROA:241 |
Pi-Alkyl |
|||
|
12. |
71597391 |
-9.3 |
PROD:120, LYSD:119, CYSD:168, LYSD:167, LEUD:87, VALD:169, LEUD:170, CYSE:180, VALE:179, PROD:47, THRE:181, PROE:183, THRD:90, LYSD:115. |
Van der Waal |
|
VALD:118, SERD:117 |
Conventional Hydrogen Bond |
|||
|
13. |
6427349 |
-9.2 |
GLND:49, ARGD:52, SERD:88, THRD:90, LEUD:87, VALD:169, VALD:118, SERD:117, SERD:150, LYSD:119, PROD:120, LYSD:167, CYSE:180, CYSD:168, PROE:183 |
Van der Waal |
|
PHED:46 |
Pi-Sigma |
|||
|
PROD:47 |
Alkyl |
|||
|
PROD:47 |
Pi-Alkyl |
|||
|
14. |
44258296 |
-9.1 |
GLNA:43, PHEA:36, SERA:71, ASPE:58, GLNA:72, GLYE:55, VALE:56, ARGE:34, THRE:75, GLND:105, GLYD:102 |
Van dar Waal |
|
TYRE:35 |
Conventional Hydrogen Bond |
|||
|
GLYD:103 |
Carbon Hydrogen Bond |
|||
|
TYRE:54 |
Pi-Pi Stacked |
|||
|
ARGA:65, ALAA:69, LYSA:68 |
Pi-Alkyl |
|||
|
15. |
12302182 |
-9.0 |
GLND:49, ARGD:52, SERD:88, THRD:90, LEUD:87, VALD:169, VALD:118, SERD:117, SERD:150, LYSD:119, PROD:120, LYSD:167, CYSE:180, CYSD:168, PROE:183 |
Van der Waal |
|
PHED:46 |
Pi-Sigma |
|||
|
PROD:47 |
Alkyl |
|||
|
PROD:47 |
Pi-Alkyl |
|||
|
16. |
1203 |
-8.8 |
SERA:38, GLUA:19, SERA:71, ASPE:58, ARGA:65, TYRE:35, GLYE:55, GLNA:72, ARGA:75 |
Van der Waal |
|
GLND:105 |
Conventional Hydrogen Bond |
|||
|
GLYD:103 |
Carbon Hydrogen Bond |
|||
|
ARGE:34 |
Unfavorable Donor-Donor |
|||
|
TYRE:54 |
Pi-Pi Stacked |
|||
|
LYSA:68, ALAA:69 |
Pi-Alkyl |
|||
|
17. |
122850 |
-8.8 |
GLUA:19, SERA:71, ARGA:65, GLYD:103, GLND:105, GLYD:102 |
Van der Waal |
|
ASPE:58, LYSA:68, GLNA:72, TYRE:35 |
Conventional Hydrogen Bond |
|||
|
ARGA:75 |
Unfavorable Donor-Donor |
|||
|
TYRE:54 |
Pi-Pi Stacked |
|||
|
ARGE:34, ALAA:69 |
Pi-Alkyl |
|||
|
18. |
10208 |
-8.8 |
LYSA:68, TYRE:35 |
Conventional Hydrogen Bond |
|
ASPE:58 |
Unfavorable Acceptor-Acceptor |
|||
|
TYRE:54 |
Pi-Pi Stacked |
|||
|
ALAA:69 |
Alkyl |
|||
|
ARGA:65, ARGE:34 |
Pi-Alkyl |
|||
|
19. |
5280343 |
-8.8 |
GLUA:19, ARGA:75, SERA:71, GLND:105, ASPE:58, LYSA:68 |
Conventional Hydrogen Bond |
|
GLYD:103 |
Unfavorable Donor-Donor |
|||
|
GLNA:34 |
Pi-Sigma |
|||
|
TYRE:54 |
Pi-Pi Stacked |
|||
|
ARGE:34 |
Pi-Alkyl |
|||
|
20. |
5281717 |
-8.8 |
TYRE:35, GLND:105, GLYD:102, GLYD:103, ASPE:58, ARGA:65, SERA:71, ARGA:75, GLUA:19 |
Van dar Waal |
|
GLNA:72 |
Conventional Hydrogen Bond |
|||
|
TYRE:54 |
Pi-Pi T-Shaped |
|||
|
LYSA:68, ALAA:69, ARGE:34 |
Pi-Alkyl |
|||
|
21. |
548970 |
-8.7 |
GLYE:55, ASPE:58, ARGA:65, GLYD:103, GLND:105, GLNA:72, GLUA:19 |
Van der Waal |
|
TYRE:35, SERA:71 |
Conventional Hydrogen Bond |
|||
|
ALAA:69 |
Carbon Hydrogen Bond |
|||
|
ARGE:34 |
Unfavorable Donor-Donor |
|||
|
ARGA:75 |
Pi-Cation |
|||
|
TYRE:54 |
Pi-Pi Stacked |
|||
|
LYSA:68 |
Pi-Alkyl |
|||
|
22. |
44258302 |
-8.7 |
DPHE:46, DLYS:115, DGLN:45, DALA:91, DTYR:94, EGLY:46, DILE:15, EGLY:44, EPRO:43, EASP:42, EVAL:92 |
Van der Waal |
|
DSER:48 |
|
|||
|
EGLN:41 |
Carbon Hydrogen Bond |
|||
|
DPRO:47 |
Pi-Donor Hydrogen Bond |
|||
|
DVAL:92 |
Alkyl Conventional Hydrogen Bond |
|||
|
DLYS:112, ETRP:119 |
Pi-Alkyl |
|||
|
23. |
5280863 |
-8.7 |
GLUA:19, LYSA:68, ASPE:58, GLND:105, TYRE:35 |
Conventional Hydrogen Bond |
|
ARGE:34, GLYD:103 |
Unfavorable Donor-Donor |
|||
|
TYRE:54 |
Pi-Pi Stacked |
|||
|
ALAA:69 |
Pi-Alkyl |
|||
|
24. |
10207 |
-8.6 |
VALE:56, TYRE:35, GLND:105 |
Conventional Hydrogen Bond |
|
ARGA:65 |
Carbon Hydrogen Bond |
|||
|
LYSA:68 |
Unfavorable Donor-Donor |
|||
|
ASPE:58 |
Unfavorable Acceptor-Acceptor |
|||
|
TYRE:54 |
Pi-Donor Hydrogen Bond |
|||
|
GLYE:55 |
Pi-Sigma |
|||
|
ALAA:69 |
Pi-Pi Stacked |
|||
|
ARGE:34 |
Pi-Alkyl |
|||
|
25 |
5319924 |
-8.5 |
ASPA:30, GLNA:32, GLYA:239, THRA:31, THRA:128, SERB:56, ASPB:54, LEUB:65 |
Van dar Waal |
|
TYRB:64, TYRA:27, ARGA:48 |
Conventional Hydrogen Bond |
|||
|
SERB:53 |
Pi-Donor Hydrogen Bond |
|||
|
ALAA:49, TRPA:51, PROA:50 |
Alkyl |
|||
|
PHEA:241, PROA:235, LEUB:66 |
Pi-Alkyl |
|||
|
26. |
222284 |
-8.3 |
PHED:46, GLND:47, SERD:48, PROD:47, GLNE:184, SERE:91, TRPE:119, HISE:163, ASPE:162, THRE:90, THRE:121, PROE:43, ASPE:42, GLNE:41, PHEE:94 |
Van der Waal |
|
GLND:49 |
Conventional Hydrogen Bond |
|||
|
|
Unfavorable Donor-Donor |
|||
|
PROE:161, PHEE:160 |
Alkyl |
|||
|
VALE:92, TYRE:197 |
Pi-Alkyl |
|||
|
27. |
5281671 |
-8.2 |
HISE:45, ARGE:48, ARGE:40, SERE:88, SERE:87, LYSE:187, ASPE:194, THRE:121, LEUE:120, HISE:163, TPRE:119, VALE:92, SERE:91, PROE:43 |
Van dar Waal |
|
THRE:90, ASNE:193, TYRE:197 |
Conventional Hydrogen Bond |
|||
|
ASPE:42 |
Pi-Anion |
|||
|
THRE:193 |
Pi-Sigma |
|||
|
28. |
5458461 |
-8.1 |
ASPA:238, GLYA:237, GLYA:239, TYRB:68, GLNA:32, ASPA:30, LEUB:65. |
Van der Waal |
|
THRA:31 |
Carbon Hydrogen Bond |
|||
|
TYRA:27, SERB:53 |
Pi-Donor Hydrogen Bond |
|||
|
LEUB:66 |
Pi-Pi T-shaped |
|||
|
ARGA:48, PHEB:241 |
Alkyl |
|||
|
TYRB:64, PROA:235 |
Pi-Alkyl |
|||
|
29. |
62344 |
-8.0 |
ARGA:6, ASPA:30, THRA:31, GLNA:32, LEUB:66 |
Van der Waal |
|
TYRA:27, TYRB:64 |
Pi- Donor Hydrogen Bond |
|||
|
PHEA:241 |
Pi-Pi T- shaped |
|||
|
PROA:235 |
Alkyl |
|||
|
ALAA:211 |
Pi- Alkyl |
|||
|
30. |
5319892 |
-8.0 |
GLNA:43, GLYE:55, LYSE:57, THRE:75, TYRE:35, GLNA:72, ARGA:75, GLYD:103, GLND:105, GLYD:102, GLUA:19 |
Van dar Waal |
|
31. |
12305761 |
-7.9 |
VALE:56, ASPE:58, GLNA:72, SERA:71 |
Conventional Hydrogen Bond |
|
ALAA:69, GLUA:19 |
Carbon Hydrogen Bond |
|||
|
LYSA:68 |
Pi-Alkyl |
|||
|
32. |
160482 |
-7.4 |
TYRE:113, THRE:111 |
Conventional Hydrogen Bond |
|
GLUE:102 |
Unfavorable Acceptor-Acceptor |
|||
|
VALD:62, ALAA:149 |
Alkyl |
|||
|
33. |
12760132 |
-7.4 |
TYRE:113, THRE:111 |
Conventional Hydrogen Bond |
|
VALD:62, ALAA:149 |
Alkyl |
|||
|
34. |
5318998 |
-7.3 |
SERD:48, PHEE:94, SERD:16, ILED:15, LYSD:112, GLYE:46, ALAD:91 |
Van dar Waal |
|
GLNE:41, TYRD:94 |
Conventional Hydrogen Bond |
|||
|
VALE:92, TRPE:119 |
Alkyl |
|||
|
VALD:92, LYSD:115, PROD:47 |
Pi-Alkyl |
|||
|
35. |
14710 |
-7.1 |
LYSE:57, ASPE:58, VALE :56, GLYE:55, ALAA :69, TYRE :35, GLND:105, GLYD:103, GLNA:72, GLUA:19 |
Van dar Waal |
|
TERE:54 |
Pi-Pi Stacked |
|||
|
LYSA:68 |
Alkyl |
|||
|
ARGE:34 |
Pi-Alkyl |
|||
|
36. |
5281426 |
-6.6 |
TRPE:119, PHEE:94, GLNE:41, ASPE:42, PROE:43, GLND:45, PROD:47, PHED:46 |
Van der Waal |
|
SERD:49, GLND:49 |
Conventional Hydrogen Bond |
|||
|
VALE:92 |
Pi-Alkyl |
|||
|
37. |
6047 |
-6.5 |
ARGE:34, ARGA:75, TYRE:35, ASPE:58, GLND:105, GLYD:103, ARGA:65 |
Van der waal |
|
GLNA:72 |
Conventional hydrogen bond |
|||
|
LYSA:68 |
Unfavorable Acceptor-Acceptor |
|||
|
LYSA:68 |
Unfavorable Donor-Donor |
|||
|
TYRE:54 |
Pi-Pi Stacked |
|||
|
ALAA:69 |
Pi-Alkyl |
|||
|
38. |
5280794 |
-6.4 |
LYSD:61 |
Conventional Hydrogen Bond |
|
ALAA:149, VALD:62 |
Alkyl |
|||
|
39. |
160190 |
-6.3 |
ASND:107, SERD:104, ASPD:38 |
Conventional Hydrogen Bond |
|
VALD:97 |
Carbon Hydrogen Bond |
|||
|
LYSD:10 |
Unfavorable Donor-Donor |
|||
|
LEUD:99 |
Pi-Sigma |
|||
|
40 |
26049 |
-5.7 |
LEUE:203, SERE:177, GLYE:178, METD:172, SERD:174, ARGE:204 |
Van der Waal |
|
VALE:205, VALE:170 |
Alkyl |
|||
|
PHEE:209, VALE:175 |
Pi-Alkyl |
|||
|
41. |
93781 |
-5.6 |
GLYD:103, ARGA:65, GLND:105, ALAA:69, GLNA:72, ARGA:75 |
Van der Waal |
|
TYRE:35 |
Conventional Hydrogen Bond |
|||
|
TYRE:54 |
Pi-Sigma |
|||
|
LYSA:68, ARGE:34 |
Pi-Alkyl |
|||
|
42. |
7213 |
-5.6 |
GLYD:102, GLYD:103, GLNA:72, ASPE:58 |
Van der Waal |
|
TYRE:35, GLND:105 |
Conventional Hydrogen Bond |
|||
|
LYSA:68, ALAA:69 |
Carbon Hydrogen Bond |
|||
|
TYRE:54 |
Pi-Pi Stacked |
|||
|
ARGA:65 |
Pi-Alkyl |
|||
|
43. |
1183 |
-5.6 |
GLNA:72, GLND:105, GLYD:103, ARGA:65, ASPE:58 |
Van der Waal |
|
TYRE:35, LYSA:68 |
Conventional Hydrogen Bond |
|||
|
TYRE:54 |
Pi-Pi Stacked |
|||
|
ALAA:69 |
Alkyl |
|||
|
ALAA:69 |
Pi-Alkyl |
|||
|
44. |
3840 |
-5.5 |
ALAA:90, PROA:15, SERA:88, ARGA:75, LEUA:78, PROA:20 |
Van der Waal |
|
GLYA:91, GLUA:89, SERA:13, HISA:93, GLYA:78 |
Conventional Hydrogen Bond |
|||
|
ARGA:82 |
Pi-Alkyl |
|||
|
45 |
785 |
-5.4 |
GLYD:102, GLND:105 |
Van dar Waal |
|
GLYD:103, TYRE:35 |
Conventional Hydrogen Bond |
|||
|
ASPE:58 |
Unfavorable Donor-Donor |
|||
|
LYSA:68 |
Unfavorable Acceptor-Acceptor |
|||
|
TYRE:54 |
Pi-Pi Stacked |
|||
|
ALAA:69, ARGA:65 |
Pi-Alkyl |
|||
|
46. |
5312441 |
-5.3 |
ASPB:54, LEUB:66, GLYA:237, GLYA:239, GLNA:32, THRA:31, ASPA:30 |
Van der Waal |
|
TYRA:27, SERB:53 |
Conventional Hydrogen Bond |
|||
|
TYRB:64 |
Alkyl |
|||
|
PROA:235, PHEA:241 |
Pi-Alkyl |
|||
|
47. |
2266 |
-5.0 |
VALE:175, LEUE:203, GLYE:178, METD:172 |
Van dar Waal |
|
ARGE:204, SERD:174, SERE:177, SERE:206 |
Conventional Hydrogen Bond |
|||
|
VALE:170, VALE:205 |
Alkyl |
|||
|
PHEE:205 |
Pi-Alkyl |
|||
|
48. |
985 |
-4.6 |
GLNA:32, ASPA:30, ARGA:6, LYSB:59, SERB:58, TYRB:27, ARGA:234, THRA:233 |
Van der Waal |
|
TYRA:27 |
Conventional Hydrogen Bond |
|||
|
TYRB:64, PHEA:241 |
Alkyl |
|||
|
ALAA:211, PROA:235 |
Pi-Alkyl |
|||
|
49 |
679 |
-3.0 |
GLYC:4, TYRA: 159, THRA:163, GLNA:155, THRD:36, ALAA:158 |
Van dar Waal |
|
ASPC:3 |
Attractive Charge |
|||
|
ASND:37, THRC:5 |
Conventional Hydrogen Bond |
|||
|
TYRD:101 |
Pi- Sulfur |
|||
|
50 |
284 |
-2.8 |
GLYD:111, THRD:12, THRD:11, LEUD:96 |
Van der Waal |
|
LYSD:112, GLYD:113, CYSD:95, PHED:110 |
Conventional hydrogen bond |
|||
|
GLND:13 |
Unfavorable Acceptor-Acceptor |
Fig 1: 2D and 3D interaction of 18 Beta Glycyrrhetinic Acid
Fig 2: 2D and 3D interaction of Muberrofurnon
DRUG-LIKENESS AND ADMET PREDICTION:
The predicted Pharmacokinetics ADMET properties and drug likeness properties of the top 10 docked phytoconstituents with the having lower binding energy are presented Table 2 and 3. pkCSM was used for the characterization of the ADMET profile of docked phytoconstituents and swissADME was used for the characterisation of Lipinski rule.
Table 2: ADMET properties of phytochemicals by PkCSM
|
Sr. No. |
Pub chem Id |
Absorption |
Distribution |
Metabolism |
Excretion |
Toxicity |
|||||||||||
|
Intestinal Absorp-tion (Human) |
P- Glyco protein Subs trate |
P- Glyco protein Subs trate I |
P- Glyco protein Sub strate II |
VDss (Human) |
BBB Perme-ability |
CNS Perme-ability |
Substrate |
Inhibitors |
Total Clearance |
AMES Toxicity |
|||||||
|
CYP |
|||||||||||||||||
|
2D6 |
3A4 |
1A2 |
2C19 |
2C9 |
2D6 |
3A4 |
|||||||||||
|
Numeric (% Absorb ed) |
Cate gorial (Yes/No) |
Cate gorial (Yes/No) |
Categorial (Yes/No) |
Numeric (log Lkg-1) |
Numeric (log BB) |
Numeric (log PS) |
|
Numeric (log mL min-1 kg-1) |
Cate-gorial (Yes/ No) |
||||||||
|
1 |
14982 |
0 |
Yes |
No |
No |
-0.576 |
-1.553 |
-4.3 |
No |
No |
No |
No |
No |
No |
No |
-0.304 |
No |
|
2 |
5281667 |
-2.892 |
Yes |
Yes |
Yes |
-1.08 |
-2.061 |
-3.314 |
No |
Yes |
No |
No |
No |
No |
No |
-1.583 |
No |
|
3 |
9959532 |
100 |
Yes |
Yes |
Yes |
-1.846 |
-1.269 |
-2.949 |
No |
Yes |
No |
No |
No |
No |
No |
1.235 |
No |
|
4 |
44258661 |
100 |
Yes |
Yes |
Yes |
-0.328 |
1.247 |
-2.844 |
No |
Yes |
No |
Yes |
Yes |
No |
Yes |
0.74 |
No |
|
5 |
503737 |
46.076 |
Yes |
No |
No |
-0.162 |
-1.146 |
-3.866 |
No |
No |
No |
No |
No |
No |
No |
0.342 |
Yes |
|
6 |
184877 |
55.365 |
Yes |
Yes |
Yes |
-o.41 |
-1.64 |
-3.345 |
No |
Yes |
No |
No |
No |
No |
No |
0.122 |
No |
|
7 |
15231527 |
87.976 |
Yes |
Yes |
Yes |
-0.412 |
-1.163 |
-1.917 |
No |
Yes |
Yes |
Yes |
Yes |
No |
No |
0.44 |
No |
|
8 |
102004551 |
75.494 |
Yes |
Yes |
Yes |
0.128 |
-1.085 |
-2.364 |
No |
Yes |
No |
No |
Yes |
No |
No |
0.327 |
No |
|
9 |
10740797 |
100 |
No |
Yes |
Yes |
0.023 |
-0.636 |
-2.988 |
No |
Yes |
No |
Yes |
Yes |
No |
Yes |
-0.349 |
Yes |
|
10 |
5481969 |
94.121 |
Yes |
Yes |
Yes |
0.001 |
-0.293 |
-1.632 |
No |
Yes |
Yes |
Yes |
Yes |
No |
Yes |
0.138 |
No |
Table 3: Drug-Likeness properties of phytochemicals by Swiss ADME
|
Sr No. |
PubChem ID |
MW (g/mol) |
mLogP |
HBA |
HBD |
MR |
TPSA |
nRot |
Lipinski's Rule (Ro5) |
Veber's Rule |
Ghose's Rule |
Egan's Rule |
Muegge's Rule |
|
1 |
14982 |
806.93 |
-0.06 |
15 |
7 |
201.27 |
246.81 |
7 |
No |
No |
No |
No |
No |
|
2 |
5281667 |
692.71 |
1.59 |
15 |
8 |
193.25 |
209.12 |
7 |
No |
No |
No |
No |
No |
|
3 |
9959532 |
209.12 |
3.21 |
8 |
5 |
155.79 |
132.75 |
2 |
Yes |
Yes |
No |
No |
No |
|
4 |
44258661 |
410.46 |
2.19 |
6 |
3 |
119.99 |
100.13 |
5 |
Yes |
Yes |
Yes |
Yes |
No |
|
5 |
503737 |
401.39 |
-0.14 |
8 |
4 |
99.45 |
125.68 |
4 |
Yes |
Yes |
Yes |
Yes |
Yes |
|
6 |
184877 |
626.61 |
0.95 |
11 |
8 |
167.11 |
205.21 |
5 |
No |
No |
No |
No |
No |
|
7 |
15231527 |
422.47 |
2.09 |
6 |
4 |
123.45 |
111.13 |
5 |
Yes |
Yes |
Yes |
Yes |
No |
|
8 |
102004551 |
492.60 |
3.19 |
6 |
4 |
144.59 |
107.22 |
8 |
Yes |
Yes |
No |
No |
No |
|
9 |
10740797 |
378.42 |
2.52 |
5 |
2 |
111.88 |
79.90 |
2 |
Yes |
Yes |
Yes |
Yes |
No |
|
10 |
5481969 |
254.24 |
1.08 |
4 |
2 |
71.97 |
70.67 |
1 |
Yes |
Yes |
Yes |
Yes |
Yes |
CONCLUSION:
Skin pigmentation, which refers to how much melanin the body generates, determines the color of the skin. The results of the molecular docking tests done in this study showed that the best performing compounds were 18 Beta Glycyrrhetinic Acid, Muberrofurnon, Artonin M, Liquiritin, Kuwanon T, Kuwanon G, Kuwanon L. Some of these compounds are, however, desirable for further evaluation due to their ADMET features. They are considered safe for usage because they do not have high BBB and CNS values, which indicate that they cannot easily access the nervous system.
REFERENCE:
1. Nautiyal A, Wairkar S. Management of hyperpigmentation: Current treatments and emerging therapies. Pigment Cell and Melanoma Research. 2021 Nov; 34(6):1000-14.
2. Nieuweboer‐Krobotova L. Hyperpigmentation: types, diagnostics and targeted treatment options. Journal of the European Academy of Dermatology and Venereology. 2013 Jan; 27: 2-4.
3. Rigopoulos D, Gregoriou S, Katsambas A. Hyperpigmentation and melasma. Journal of Cosmetic Dermatology. 2007 Sep; 6(3): 195-202.
4. Thawabteh AM, Jibreen A, Karaman D, Thawabteh A, Karaman R. Skin pigmentation types, causes and treatment—a review. Molecules. 2023 Jun 18; 28(12): 4839.
5. Zheng ZP, Tan HY, Wang M. Tyrosinase inhibition constituents from the roots of Morus australis Fitoterapia. 2012 Sep 1; 83(6): 1008-13.
6. Kothapalli L, Sawant P, AshaThomas RW, Bhosale K. Understanding the Molecular Mechanism of Phytoconstituents as Tyrosinase Inhibitors for Treatment of Hyperpigmentation. Saudi J. Med. Pharm. Sci. 2021; 7: 135-44.
7. Clark AK, Sivamani RK. Phytochemicals in the treatment of hyperpigmentation. Botanics: Targets and Therapy. 2016 Sep 16: 89-96.
8. Briganti S, Camera E, Picardo M. Chemical and instrumental approaches to treat hyperpigmentation. Pigment Cell Research. 2003 Apr; 16(2): 101-10.
9. Shinde G, Thombre A, Bhadalekar M, Chougule N, Shelke B, Shinde S. Molecular Docking, Drug likeness Studies and ADMET Prediction of Phytochemical of plant Ipomoea Tricolor for Breast Cancer Activity. Asian Journal of Pharmaceutical Research. 2025 May 5; 15(2):97-103.
10. Shelke B, Thombre A, Bhadalekar M, Chougule N, Shinde G, Shinde S. In Silico ADMET and Molecular Docking Study on Searching Potential Inhibitor from Bambusa Bambos for Urinary Tract Infection. Asian Journal of Pharmaceutical Research. 2025 May 5; 15(2):114-20.
|
Received on 29.04.2025 Revised on 16.08.2025 Accepted on 23.10.2025 Published on 20.01.2026 Available online from January 27, 2026 Asian J. Pharm. Tech. 2026; 16(1):5-12. DOI: 10.52711/2231-5713.2026.00002 ©Asian Pharma Press All Right Reserved
|
|
|
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License. |
|