INTRODUCTION:

Cancer is a class of complex disease basically caused by uncontrolled cell growth. It is considered to be one of the deadliest and also poses a serious threat to human life, one of the leading causes of death worldwide^1,2. Till date there are very limited treatment options available to combat cancer. Moreover, the high price of advanced anticancer drugs available in the market is not affordable to majority of patients in poor and developing countries². Therefore, discovery of novel, cost-effective anti-cancer therapeutics is an urgent need. Researchers are trying hard to find novel anti-cancer agents with better efficacy, lesser side effects and also which is cost effective.

Various phytocompounds have shown their anticancer potential experimentally^3,4,For example, plant such as Scutellaria baicalensis, Verbascum lychnitis, Aristotelia chilensis, Isodon eriocalyx and Citrus aurantium contains multiple phytochemicals having potential anticancer properties^5-8. Combinatorial use of phytochemical and conventional chemotherapeutic agents can potentially intensify the therapeutic effects while minimizing adverse side effects⁹. Continued advancements in this field are essential for overcoming the challenges encountered in the development of anticancer therapeutics from natural sources. Nowadays other than conventional anti-cancer treatment, many phytocompounds are also already being used to treat cancer or as a supportive care in cancer^10,11.

Phytocompounds are biologically active compounds which are present in plant materials^11,12. They have properties that prevent diseases and provide protection^12-16. Knowledge of traditional medicines or ethno- medical information passes from one generation to another which makes the basis for current advanced research on drug discovery from natural resources. The chemopreventive and anticancer therapeutic properties of numerous medicinal plants have been reported^17,18. Numerous studies including invitro experiments with cell cultures, animal model studies, and clinical trials have shown that many phytocompounds possesses pro- apoptotic, anti-proliferative and anti-metastatic effects¹⁸. Phytocompounds have also been found to possess anti- inflammatory, anti-bacterial, antiviral, and free radical scavenging properties that help fight cancer. Phytocompounds can modulate different signaling pathway which regulate the replication and death of different types of tumor cell through various mechanisms^19,20. Phytotherapies are considered to be less toxic to normal cells and cytotoxic to cancer cells. Additionally, phytomedicines may be an option for cancer prevention and treatment both with and without conventional drugs. In cases where conventional cancer drugs are not suitable due to their side effects or low effectiveness, phytomedicines can offer a safe and cost-effective alternative. The use of phytomedicines can also be considered as an alternative to conventional cancer therapies for patients not getting any benefits or suffer side effects from them.

In search of novel anticancer therapeutics, phytocompounds can be tested against previously less explored human proteins. Many studies have explained that human UPF1 protein has significant role in tumor promotion and control in human²¹. In general, UPF1 is considered to be one of the highly significant factors of nonsense-mediated mRNA decay (NMD) pathway. NMD is a post transcriptional mRNA quality control mechanism, which is found to be highly evolutionary conserved among all eukaryotes^22,23. NMD acts by removing or degrading PTC containing aberrant mRNAs, thereby preventing the production and accumulation of truncated proteins and protecting cells from its deleterious effects. NMD modulates significant cellular processes and helps to maintain cellular homeostasis.

Role of UPF1 in NMD pathway:

UPF1 is a common RNA-binding protein which is found to be evolutionary highly conserved in almost all eukaryotes. It was first identified in S. cerevisiae²⁴. It is an RNA helicase protein, which is considered to be the central regulator of NMD pathway²⁵. Because of its helicase activity UPF1 can translocate from 5’ to 3’ on a single stranded nucleic acids, unwind duplexes and disrupts RNA-protein interactions. UPF1 is involved in many other pathways such as replication dependent histone mRNA decay (HMD), regnase-1 mediated mRNA decay (RMD), glucocorticoid receptor-mediated mRNA decay (GMD) etc. The gene of human nmd protein UPF1 is found to be located at chromosome19. Analysis of sequence of UPF1 shows that it contains two evolutionary conserved functional regions, one is N-terminal cysteine rich domain and the other is C-terminal helicase domain^26,27. Many studies have shown that in certain tumor types including colorectal cancer, lung adenocarcinoma and endometrial carcinoma^28,29,30. UPF1promotes tumerogenesis and knockdown of UPF1 triggers apoptosis in those tumor cells³¹. So by modulating or inhibiting the human UPF1 (hUPF1) protein we can change the process of tumor progression in certain tumor types. Different studies have explained that UPF1 shows both pro tumor and anti tumor activity depending upon cancer types. The biological role of UPF1in cancer is not yet fully understood. In this study our focus is on the pro tumor activity of this NMD factor UPF1 in human.

MATERIALS AND METHODS:

A flowchart diagram of this current study of screening of phytochemicals against the helicase domain of human UPF1 protein is presented in Figure 1.

Figure 1: Representing flow chart of the study of identifying the potential inhibitors of hUPF1 using molecular docking approach and in silico ADME analysis.

Selection and processing of ligand:

Based on literature survey we have selected and prepared a library of 50 bioactive phytochemicals having anticancer potential. Chemical structures of these 50 phytochemicals were obtained from the PubChem database in SDF format. Before proceed to molecular docking step, energy minimization and optimization of these phytochemicals were done using openbabel in linux environment³². Then these compounds were converted and saved in pdbqt format.

Preparation of receptor protein (UPF1):

The three dimensional (3D) structure of the helicase domain of human UPF1 protein (PDB ID: 2GJK) was downloaded from the RCSB Protein Data Bank for docking purposes. Prior to docking we have processed the 3D structure of this human UPF1 protein using AutoDockTools^33,34. In this preprocessing step removal of water molecule and other hetero atoms were done, added polar hydrogens and Kollman charges. Then generated grid box with the dimension of 126 Å × 126 Å × 126 Å and kept other parameters as default.

Molecular Docking based screening of potential inhibitor of UPF1:

For this molecular docking study, we have used AutoDock Vina³⁵ version 1.2.3. To screen for potential inhibitors of human UPF1, performed a blind docking of the library of 50 bioactive phytocompounds against the helicase domain of the human UPF1 protein.

Drug-likeness and ADME profiling:

Phytocompounds screened through molecular docking study has undergone in silico ADME analysis using Swiss ADME server^36-38. In this analysis we have checked for any violations of both Lipinski’s rule³⁹ and Veber’s rule⁴⁰ along with other parameters.

RESULTS AND DISCUSSION:

Molecular docking:

In computational drug designing molecular docking is a widely used method that helps to identify potential drug candidates against various disease targets. This advanced computational method can save a significant amount of energy, time, and costs in the drug discovery process by screening large libraries of potential drug compounds in a very short span of time. In our study, we have screened a library of 50 bioactive phytocompounds against human UPF1 using Autodock Vina 1.2.3. Based on the docking score, we have shortlisted 8 bioactive phytochemicals, namely, Silibinin, Baicalein, Luteolin, Delphinidin, Eriocalyxin B, Aspalathin, Hesperetin and Diosquinone which are found to have a higher binding energy of -9.247, -8.858, -8.682, -8.453, -8.321, -8.276, -8.004 and -7.906 kcal/mol, respectively. The potein-ligand binding affinity and details of various molecualr interactions of these eight top screened compounds with human UPF1 are displayed in Table 1.

Table 1: Results of molecular docking showing binding affinity and various molecular interactions between hUPF1 and top screened phytocompounds

Sl. No	Phytomolecule	Binding Affinity (kcal/mol)	Number of hydrogen bond	Residues involved in different types of molecular interactions
1	Silibinin	-9.247	3	Hydrogen bond: GLU313, SER548, ASP524
				Pi-Alkyl: VAL618, ALA546
				Van der Waals Interaction:
				ASP317, VAL670, MET671, VAL669, PHE420, VAL 310,
				LEU 680, THR642, MET423, SER419, GLU645, GLY359,
				ARG422, THR616, MET357
2	Baicalein	-8.858	1	Hydrogen bond: ARG703
				Carbon–hydrogen bond: GLY495
				Pi–sigma: VAL500
				Pi-Alkyl: PRO 469
				Pi-Anion: GLU833
				Pi-Pi Stacked: 702
				Van der Waals Interaction:
				MET628,LEU652,PRO623,ASP622,ARG422,SER 425,VAL651
3	Luteolin	-8.682	3	Hydrogen bond: GLN475, GLY831, and GLN529
				Carbon–hydrogen bond: GLY497
				Pi–sigma: VAL500
				Pi-Alkyl: PRO 469, VAL500
				Pi-Cation: LYS533
				Pi-Pi Stacked: TYR702
				Van der Waals Interaction:
				ASN472, LEU471,ASP470,GLU833,ARG832,ARG703,THR499
4	Delphinidin	-8.453	3	Hydrogen bond: GLY831, GLN475 and THR499
				Carbon–hydrogen bond: GLY497
				Pi–sigma: VAL500
				Pi-Alkyl: PRO 469, VAL500
				Pi-Pi Stacked: GLY495
				Van der Waals Interaction:
				ARG832, GLN529, GLU833, LYS498, LEUU471,
				ASN472
5	Eriocalyxin	-8.321	2	Hydrogen bond: GLU361 and SER419
				Carbon–hydrogen bond: GLY497
				Van der Waals Interaction:
				ASP360, GLY359, SER548, ALA546, ARG422, VAL618,
				THR418, MET 357, TRP415, PHE420
6	Aspalathin	-8.276	2	Hydrogen bond: GLU645
				Pi-Alkyl: LYS416
				Pi-Anion: ASP360
				Pi-Pi T-shaped: PHE420
				Van der Waals Interaction:
				THR642, VAL669, PRO522, SER523, MET671, AS317,
				MET354, TRP45, LYS321, GLY359, SER548, NAL414
7	Hesperetin	-8.004	2	Hydrogen bond: ARG703 and GLN475
				Carbon–hydrogen bond: GLY831
				Pi–sigma: VAL500
				Pi-Alkyl: PRO 469, VAL500
				Pi-Anion: GLU833
				Pi-Pi Stacked: TYR702
				Van der Waals Interaction:
				ASP470, ASN472, GLY497, GLY495, THR499, GLN529
8	Diosquinone	-7.906	4	Hydrogen bond: GLN629, LYS627, GLY621 and THR429
				Carbon–hydrogen bond: GLY831
				Pi-Alkyl: ALA426, ALA626, VAL648
				Pi-Anion: ASP433
				Van der Waals Interaction:
				Met628,Leu652,Pro623,Asp622,Arg422,Ser 425,Val651

Table 2: ADME properties of screened top eight phytochemicals

SI. NO.	Phytochemical	MW (g/mol)	Conesenus Log Po/w	No. of H bond acceptors	No. of H bond donors	Molar refractivity	Lipinski
1.	Silibinin	482.44	1.59	10	5	120.55	NO
2.	Baicalein	270.24	2.24	5	3	73.99	YES
3	Leteolin	286.24	1.73	6	4	76.01	YES
4.	Delphinidin	338.7	-0.98	7	6	84.05	YES
5.	EriocalyxinB	344.4	1.68	5	2	89.8	YES
6.	Aspalathin	452.41	-0.49	11	9	108.66	NO
7.	Hespertetin	302.28	1.91	6	3	78.06	YES
8.	Diosquinone	390.34	2.37	7	2	100.75	YES

Continew Table 2

SI. NO.	Phytochemical	Veber	Synthetic accessibility	Bioavailability score	TPSA	No. of rotatable bonds	Solubility (mg/ml)
1.	Silibinin	NO	4.92	0.55	155.14	4	3.46E-02
2.	Baicalein	YES	3.02	0.55	90.9	1	2.51E-02
3	Leteolin	YES	3.02	0.55	111.13	1	5.63E-02
4.	Delphinidin	YES	3.21	0.55	134.52	1	2.36E-01
5.	EriocalyxinB	YES	6.36	0.55	83.83	0	7.29E-01
6.	Aspalathin	NO	4.7	0.17	208.37	6	1.77E+00
7.	Hespertetin	YES	3.22	0.55	96.22	2	7.19E-02
8.	Diosquinone	YES	4.47	0.55	121.27	1	1.04E-02

Evaluation of drug likeness:

Top eight phytocompounds screened through molecular docking study has undergone insilico ADME analysis to check their pharmacokinetic properties. Out of these eight phytocompounds six compounds shows zero violations of Lipinski’s and Veber’s rule, so these six phytocompounds can be process further for developing new therapeutics. Other two compounds silibinin and aspalathin have shown significant binding affinity against hUPF1 in molecular docking study but both of these phytochemicals are found to be violating Lipinski’s and Vebers rule, so these two compounds cannot be used as drug candidate. Overall analysis of the drug-likeness indicates that, six phytochemicals namely Baicalein, Luteolin, Delphinidin, EriocalyxinB, Hesperetin and Diosquinone shows positive pharmacokinetic properties which makes them potential hits. The results of the insilico ADME analysis of shortlisted eight phytochemicals using Swiss ADME server are shown in Table 2.

Several phytocompounds possess the anti-cancer properties. This docking outcome indicates that many phytocompounds might interact with amino acid residues of human UPF1 protein effectively. In the present study, we explored the potential of 50 phytochemicals against the human UPF1 (helicase domain) and based on the molecular docking results and in silico analysis of ADME properties six natural compounds were selected, namely, Baicalein, Luteolin, Delphinidin, EriocalyxinB, Hesperetin and Diosquinone for further evaluation.

In this study we have used Biovia Discovery visualizer to generate 2D and 3D plots of molecular interactions between protein and ligands. The 3D plot mainly shows the different bonded interactions. To show the various bonded as well as non-bonded (eg. Van der Waals) molecular interactions between hUPF1 and phytocompounds we have generated 2D plot. Here we have shown both 3D and 2D plots of of molecular interactions between protein and the selected ligands with high binding affinity (Figure 2 and 3 [A to F]).

Figure 2: 2D and 3D representation of molecular interaction between the hUPF1 (PDB ID: 2GJK) and Baicalein (CID_5281605): (A) 3D structure representation of baicalein ; (B) Molecular docking complex of a crystal structure of hUPF1 with baicalein; (C) close view of pocket with baicalein structure in the stick model colored by atom types; (D) 2D representation of different types of interactions with baicalein including van der Waals, conventional hydrogen bond, carbon hydrogen bond, Pi–sigma, and alkyl; (E) hydrophobicity surface representation of the overall structure of hUPF1 in complex with baicalein ; and (F) Surface representation of the complex showing residues involved in hydrogen bond donor acceptor.

Figure 3(A to F): 2D and 3D representation of docking complexes: (A): hUPF1 and baicalein complex; (B): hUPF1 and luteolin complex; (C): hUPF1 and delphinidin complex; (D): hUPF1 and eriocalyxinB complex; (E): hUPF1 and hesperetin complex; (F): hUPF1 and diosquinone complex visualized using Discovery Studio.

CONCLUSION:

The inhibition of hUPF1 protein by potential phytochemicals can be an effective strategy for novel antcancer therapeutics development. The result of molecular docking and in silico ADME analysis supported that the phytocompounds Baicalein, Luteolin, Delphinidin, EriocalyxinB, Hesperetin and Diosquinone can be the potential inhibitors of the NMD factor hUPF1 (Figure 4). The effectiveness of these phytocompounds may be further validated through in vitro and in vivo experiment. In this study we conclude that these six compounds may be used as potential inhibitors of hUPF1 in the the process of discovering potential anticancer therapeutics. In the upcoming next few decades phytomedicines may become a choice of treatment line over conventional drugs for many diseases including cancers. Application of modern scientific technologies and knowledge of traditional medicines can be of great help in the process of developing novel anticancer phytomedicines. By incorporating phytomedicines in modern healthcare systems and promoting sustainable practices enables to address various aspects of sustainable development.

Figure 4: Possible strategy of preventing cancer by deploying phytochemicals targeting the UPF1

FUNDING:

The authors would like to thank the Vice Chancellor, Centurion University of Technology and Management, Odisha for providing financial support to GKP (grant approval letter no: CUTM/VC Office/45 to GKP).

CONFLICT OF INTEREST:

The authors declare that they have no conflict of interest.

CREDIT AUTHORSHIP CONTRIBUTION STATEMENT:

All the authors have substantial contribution for the preparation of the manuscript. GKP: conceptualized and conceived the idea. SM, RD and GKP: conducted experiments, data curation and writing. All the authors have read and approved the final manuscript before submission.

ACKNOWLEDGEMENTS:

Authors thank the administration and management of Centurion University of Technology and Management, Odisha, India for their heartfelt support. We apologize to all colleagues whose work could not be included owing to space limitations.

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Received on 04.04.2024 Revised on 12.09.2024

Accepted on 16.12.2024 Published on 28.01.2025

Available online from February 27, 2025

Research J. Pharmacy and Technology. 2025;18(2):489-494.

DOI: 10.52711/0974-360X.2025.00074

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.

Sanjoy Majumder1, Rutupurna Das2, Gagan Kumar Panigrahi2*