MOLECULAR DESIGN AND DOCKING STUDY OF NOVEL QUINOXALINE-CONTAINING COMPOUNDS AS PI3K/MTOR DUAL INHIBITOR

MOLECULAR DESIGN AND DOCKING STUDY OF NOVEL QUINOXALINE-CONTAINING COMPOUNDS AS PI3K/MTOR DUAL INHIBITOR

Sandhya Jain * and Surya Prakash Gupta

Rajiv Gandhi Institute of Pharmacy, Faculty of Pharmaceutical Sciences & Technology, AKS University Satna, Madhya Pradesh, India.

ABSTRACT: The PI3K-AKT-mTOR signaling pathway is widely used in cancer therapy as it is a signaling pathway that is frequently disrupted in human cancers. Increasingly, inhibitors develop against key proteins in signaling pathways, such as PI3K and mTOR. Dual inhibitors targeting PI3K and mTOR are more potent than one inhibitor targeting only a single protein. This study used to design and molecular docking analysis to investigate the precise binding positions and interaction forces of quinoxaline-containing compounds within the active site of PI3Kγ and mTOR with the help of freely available software for virtual screening of compounds, docking, and drug interaction result analysis. And also proposed the development of new potent drug candidates which works as dual inhibitors against cancer diseases; thus it could be concluded that Quinoxaline-containing derivatives might be used as a template for destiny improvement thru change or derivatization to lay out stronger healing agents.

Keywords: PDB, mTOR, Pi3k, Signaling Pathway, Molecular docking, Dual inhibitors

INTRODUCTION: Cancer is an epidemic worldwide, a leading cause of death worldwide, accounting for nearly 10 million deaths in 2020, or nearly one in six deaths. The most common cancers are breast, lung, colon, rectum, and prostate cancers ¹. With the worldwide devastation the sickness is wreaking, the call for brand-new and powerful drugs is inexhaustible. The position of the PI3K-AKT-mTOR signaling pathway is an essential boom signaling pathway, advancing our knowledge that its ongoing activation in numerous cancers kinds is rising as a fascinating goal for most cancers therapy ^2-5.

In recent years, there have been growing attempts to increase new inhibitors towards key signaling proteins in signaling pathways, including PI3K, AKT and Mtor ^6-11 Phosphatidylinositol-4,5-bisphosphate-3-kinase (PI3K) is a lipid and member of the serine/threonine kinase family. Produces β-triphosphate (PIP3). PI3K regulates cellular metabolism and cellular proliferation by phosphorylating downstream effectors and adapters via the second messenger, PIP3 ¹².

However, consistent activation and/or over-expression of PI3K reasons disruption of mobile characteristics main to most cancers ^13-17. PI3Ks are categorized into 3 groups ³, I, II and III, primarily based totally on their collection and substrate specificity ^18-19. Class I PI3Ks are the maximum implicated in most cancers ²⁰ and are similarly divided into Class IA and IB categories, primarily based on their regulatory subunits and activation mechanisms. Class IA PI3Ks incorporate regulatory and catalytic subunits, particularly p85 and p110. Class IA p110 subunits are located in 4 isoforms α, β, γ, and δ. All p110 catalytic subunits proportion a not unusual place fundamental shape with a C2 area, a helical area, and a catalytic area ²¹ All p110 elegance IA subunits are activated via way of means of receptor tyrosine kinases (RTKs) ²² Persistent activation of sophistication 1A PI3K via way of means of mutation is regularly detected in numerous human cancers. The cytosolic serine-threonine kinase mTOR is a member of the PI3K-associated kinase family (PIKK) ²⁴.

mTOR stands for “mammalian goal of rapamycin” and turned into so name as it turned into first observed because the mammalian homologue of a yeast protein referred to as TOR, an acronym for “goal of rapamycin ”^{25, 26}.

The kinase area of mTOR (approximately 550 residues) includes an N-terminal lobe (N-lobe) and a bigger C-terminal lobe (C-lobe) with an ATP-binding or catalytic webpage within side the cleft among them ^{27, 28}. mTOR is an appropriate drug goal for numerous forms of most cancers as it regulates cellular metabolism and cellular boom ^{29, 30}.

Rapamycin, the primarily regarded inhibitor of mTOR, pals with its intracellular receptor FKBP12 and allosterically inhibits mTOR ^{31, 32}. The FKBP12-rapamycin complicated at once interacts with the FKBP12-rapamycin binding area (FRB) to inhibit mTOR characteristics. Rapamycin binds handiest to at least one mTOR complicated, mTORC1, and inhibits handiest mTORC1-related signaling features ³³. This brought about the invention of ATP-aggressive mTOR inhibitors ³⁴ that bind to each mTORC1 and mTORC2 and inhibit the kinase-based features of mTOR ³⁵.

Quinoxaline and its derivatives are a crucial magnificence of heterocyclic compounds, they have got attracted large interest through the years thanks to their very thrilling pharmaceutical and organic homes including insecticidal, antifungal, anthelmintic, anticancer, antibacterial and antiviral ^{36, 37} and it's far formerly suggested that the quinoxaline moiety is a famous and promising scaffold with its far a crucial heterocyclic nucleus with a huge spectrum of organic activities, and these days an awful lot interest has been located on anticancer drug recognized anticancer homes.

MATERIAL AND METHOD:

To Generate the Combinatorial Library of Compounds: For the technology of the Combinatorial Library of compounds, the concept is taken from the Previously pronounced compound and picks the R1 and R2 role with specific substituents to generate the brand new compounds ³⁸.

The 9 substituents have been taken into consideration for R1 possibility from the preceding stated PI3K/mTOR inhibitors Fig. 1. Whereas five small substituents including `-O-CH3`, `-OH`, `-NH2`, `-F`, and `-Br` have been used for R2 possibility Fig. 2 and Fig. 3. These R1 and R2 replacements generate a library of favored forty compounds used on this have a look at for digital displaying with inside the course of PI3Kγ and mTOR. The compounds generated have been named as sequential numbers from 1 to twenty within the order of systematic substitution of R1 and R2 Position Table 1 and 2.

FIG. 1:  STRUCTURES OF PREVIOUSLY REPORTED DUAL MTOR/PI3K INHIBITORS

FIG. 2: TO GENERATE COM1 -COM 20

TABLE 1: STRUCTURES OF R₁ AND R₂ TO DESIGNED COM1 TO 20

Compd.	R1	R2	Compd	R1	R2
Com 1			Com 11
Com 2			Com 12
Com 3			Com 13
Com 4			Com 14
Com 5			Com 15
Com 6			Com 16
Com 7			Com 17
Com 8			Com 18
Com 9			Com 19
Com 10			Com 20

FIG. 3: TO GENERATE MOL1-MOL 20

TABLE 2: STRUCTURES OF R₁AND R₂ TO DESIGNED MOL1 TO 20

Molecules	R1	R2	Molecules	R1	R2
Mol 1			Mol 11
Mol 2			Mol 12
Mol 3			Mol 13
Mol 4			Mol 14
Mol 5			Mol 15
Mol 6			Mol 16
Mol 7			Mol 17
Mol 8			Mol 18
Mol 9			Mol 19
Mol 10			Mol 20

Data Procurement: The 3-dimensional structure of selected drugs designed from the freely available site Novoprolabs https://www.novoprolabs.com/ while the systems of proteins had been retrieved from Protein Data Bank (PDB): PI3Kγ p110 with PDB Id, 3L54 and mTOR with PDB Id, 4JT6 respectively. The kinase area of mTOR (residues from 1867 to 2436) was taken into consideration with inside the have a look at and used for all analyses. The retrieved systems had been co-complicated systems with certain ligands (PI3Kγ with certain LXX, mTOR with certain PI-103), and those certain ligands had been used as clues for catalytic grid era in molecular docking ⁴⁴.

Molecular Docking and Structure Generation: All the molecular docking simulations were carried out through Auto Dock veena v.2.1 ^{39, 40}. The pre-processing of proteins and ligands, which are referred to as shape preparation, required as enter for docking, was carried out through Chimera v.1.6.2 ⁴¹.

First, we used the Chimera to remove all HOH molecules from the protein, assign hydrogen polarities, and add Colman charges and polar hydrogen atoms. A Gas tiger charge was also applied to the generated proteins, and the protein structure file PDB was converted to PDBQT. The chemical substances had been changed the usage of Marvin Sketch v.18.4, Che Maxon https://chemaxon.com/marvin and chem-doodle.

 Analyses of Docked Protein-ligand Interaction: The docked complexes of protein and ligand had been visually analyzed through PyMOL v.1.three^42, and illustrations had been prepared. The molecular interactions among the proteins and ligands had been analyzed and illustrated through Biovia discovery studio ⁴³.

RESULTS AND DISCUSSION:

Virtual Screening of Generated Combinatorial Library: The combinatorial library of all the 40 compounds (20 compounds generated from schem1 and other 20 compounds generated from scheme 2) used for virtual screening and their dock scores for PI3Kγ and mTOR is provided in Table 3. The eight compounds (highlighted in bold in table 3) were common among top scoring compounds of PI3Kγ and mTOR Fig. 3. Generally, these eight compounds have better dock scores and binding energy. These compounds were proposed as potential dual PI3K/mTOR inhibitors.

TABLE 3: VIRTUAL SCREENING OF ALL THE LIGANDS AND THEIR DOCK SCORES FOR PI3KΓ AND MTOR

Mol.	R1	R2	Docking Score for mtor (Kcal/mol)	Docking Score for Pi3k (Kcal/mol)	Compd	Docking Score for mtor (Kcal/mol)	Docking Score for Pi3k (Kcal/mol)
Mol 1			-7.6	-5.2	Com 1	-8.0	-8.3
Mol 2			-8.0	-8.3	Com 2	-6.4	-4.2
Mol 3			-5.2	-4.6	Com 3	-5.3	-3.7
Mol 4			-10.2	-6.4	Com 4	-9.3	-6.4
Mol 5			-5.3	-6.4	Com 5	-6.4	-3.6
Mol 6			-6.4	-3.6	Com 6	-3.4	-3.4
Mol 7			-4.3	-3.4	Com 7	-1.2	-1.2
Mol 8			-5.6	-4.2	Com 8	-4.8	-4.3
Mol 9			-4.6	-4.8	Com 9	-3.4	-3.4
Mol 10			-5.5	-6.5	Com 10	-6.2	-4.6
Mol 11			-6.4	-6.2	Com 11	-5.8	-1.3
Mol 12			-7.2	-3.4	Com 12	-5.4	-3.4
Mol 13			-6.3	-1.2	Com 13	-7.4	-5.1
Mol 14			-10.2	-6.6	Com 14	-10.1	-8.4
Mol 15			-3.4	-3.4	Com 15	-4.4	-3.4
Mol 16			-1.2	-1.2	Com 16	-5.2	-1.2
Mol 17			-4.8	-4.8	Com 17	-4.8	-4.8
Mol 18			-3.4	-3.4	Com 18	-3.4	-3.4
Mol 19			-6.1	-5.9	Com 19	-8.4	-7.6
Mol 20			-5.8	-3.5	Com 20	-6.8	-4.3

FIG. 4: STRUCTURE REPRESENTATION OF EIGHT COMPOUNDS WAS PROPOSED AS A POTENTIAL DUAL PI3K/MTOR INHIBITOR

Molecular Docking Results Analysis of Eight Proposed Dual Inhibitors Interactions with Mtor: During target docking of all eight compounds, all compounds were observed to form conventional hydrogen bonds with the minimum bond length>3, and of them Com 14 and Mol 14 was observed to form the most hydrogen bonds. However, binding energies, hydrogen bond length, and the interacting residue for all eight compounds were determined, as shown in Table 4. Interestingly, Com 14 and Mol 14 exhibited the lowest binding energy of -10.1 kcal/mol and -10.2, respectively and the most common interacting residue is LYS-890. However, the binding energies shown in the table are mainly due to the chemical interactions shown in Fig. 4. Basically, chemical interactions form bonds such as covalent, alkyl, pi, and hydrogen bonds that affect the stability of protein-ligand bonds. All the compounds have 6-10 no of interactions, reflecting that the docked compound's binding poses ensure favorable and valid potential binding modes with Mtor.

TABLE 4: DOCKING RESULT ANALYSIS OF EIGHT PROPOSED COMPOUNDS FOR MTOR

FIG. 5: 2D AND 3D INTERACTIONS OF EIGHT PROPOSED COMPOUNDS WITH MTOR

Molecular Docking Results Analysis of Eight Proposed Dual Inhibitors Interactions with Pi3k: During target docking of all eight compounds, all compounds were observed to form conventional hydrogen bonds with a minimum bond length >2, and among them, Mol2 and Mol4 were found to form the most hydrogen bonds it Observed. However, the binding energies, hydrogen bond lengths, and interacting residues were determined for all eight compounds, as shown in Table 5. Interestingly, Com 14 and Mol 2 show the lowest binding energies of −8.4 kcal/mol and −8.3 kcal/mol, respectively, and the highest covalent interaction residue is met-494. However, the binding energies shown in the table are primarily due to the chemical interactions shown in Fig. 5. Basically, chemical interactions form bonds such as covalent, alkyl, pi, and hydrogen bonds that affect the stability of protein-ligand bonds. All compounds exhibit 3–10 interactions, reflecting that the binding positions of the docked compounds ensure favorable and effective potential binding modes with Pi3k.

TABLE 5: DOCKING RESULT ANALYSIS OF EIGHT PROPOSED COMPOUNDS FOR PI3K

FIG. 6: 2D AND 3D INTERACTIONS OF EIGHT PROPOSED COMPOUNDS WITH PI3K

CONCLUSION: The drug designing and molecular docking have a look at Quinoxaline containing derivatives with Mtor and pi3k twin inhibitors and discovered that Quinoxaline containing derivatives have correct interplay in a beneficial pose with Mtor and pi3k twin inhibitors, which become defined through the lowest binding energy, sturdy bond duration and 3-10 no of interactions with the energetic site. Thus it could be concluded that Quinoxaline-containing derivatives might be used as a template for destiny improvement thru change or derivatization to lay out stronger healing agents. Compounds synthesized if well modified into a healing agent may be used as an anticancer agent.

ACKNOWLEDGMENT: I would like to thank the Director of the Department, Rajiv Gandhi Institute of Pharmacy, Department of Pharmaceutical Sciences & Technology Faculty of Pharmaceutical Sciences & Technology AKS University Satna (MP) India. For providing me the opportunity and requirements needed to accomplish the research project.

Funding Source: Funding has not been received for this study.

CONFLICTS OF INTEREST: Present Article does not contain any conflict of interest.

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    How to cite this article:

    Jain S and Gupta SP: Molecular design and docking study of novel quinoxaline containing compounds as pi3k/mtor dual inhibitor. Int J Pharm Sci & Res 2023; 14(9): 4513-23. doi: 10.13040/IJPSR.0975-8232.14(9).4513-23.

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