Molecular docking studies of flavanone and its derivatives on pi3k pathway to search for potential target against cancer

Sagar Rohidas Nagare; Kiran Bharat Lokhande; Kakumani Venkateswara Swamy

doi:10.4103/jdrr.jdrr_69_19

DPU: INTERDISCIPLINARY CONFERENCE

Year : 2020 | Volume : 7 | Issue : 5 | Page : 26-29

Molecular docking studies of flavanone and its derivatives on pi3k pathway to search for potential target against cancer

Sagar Rohidas Nagare¹, Kiran Bharat Lokhande², Kakumani Venkateswara Swamy²
¹ School of Biotechnology and Bioinformatics, D. Y. Patil University, Navi Mumbai, Maharashtra, India
² Bioinformatics Research Laboratory, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, India

Date of Web Publication

26-Feb-2020

Correspondence Address:
Kakumani Venkateswara Swamy
Bioinformatics Research Laboratory, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Tathawade Campus, Tathawade, Pune - 411 033, Maharashtra
India

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/jdrr.jdrr_69_19

Abstract

Derivatives of flavanone are reported to have a major role in cell cycle arrest and metastasis and invasion and angiogenesis. Among them, PI3K-Akt pathway is a vital pathway for drug target. A co-crystal structure of Akt1 complex with substrate peptide and inhibitor Protein Data Bank (PDB ID: 3CQW) was used to study the interactions between the existing drug databases such as DrugBank, PubChem, and Zinc. Newly designed compounds were based on the modifications at the B-ring position of the core structure of flavanone. As per recent literature, the modifications at the B-ring position would enhance the stability and maintain the anticancer activity. The screened compounds were docked against Akt protein with defined grid space advance docking tool FlexX used for docking calculation. Based on the hydrogen bond and electrostatic potential interaction with targeted protein, favorable conformations were calculated. These studies would help in designing and development of new lead molecules through in silico analysis.

Keywords: Cancer, flavanones, in silico studies, molecular docking, phosphoinositide 3-kinase-Akt

How to cite this article:
Nagare SR, Lokhande KB, Swamy KV. Molecular docking studies of flavanone and its derivatives on pi3k pathway to search for potential target against cancer. J Dent Res Rev 2020;7, Suppl S2:26-9

How to cite this URL:
Nagare SR, Lokhande KB, Swamy KV. Molecular docking studies of flavanone and its derivatives on pi3k pathway to search for potential target against cancer. J Dent Res Rev [serial online] 2020 [cited 2022 Jun 28];7, Suppl S2:26-9. Available from: https://www.jdrr.org/text.asp?2020/7/5/26/278907

Editor: Dr. Sarika Chaturvedi

Introduction

Lipid kinases commonly termed phosphoinositide 3-kinases (PI3Ks) have been key regulators in the differentiation of cell survival and proliferation.^[1],[2],[3] PI3Ks is mostly responsible for transferring intracellular signals and helpful in activating serine/ threonine kinase and AKT downstream effector pathways.^[4],[5] Current finding of the human cancer genome was identified, and it proves that PI3K components are having prime role in somatic and germline mutations in human cancers and thus making PI3K pathway a potential target for pharmacologic intervention^[6],[7] [Figure 1]. Flavanone and its analogs have been reported as effective against tumorigenesis, invasion, and angiogenesis.^[8],[9] Flavanones (2-phenylchroman-4-ones) [Figure 2] are a class of natural product that shows extensive biological activities with low toxicity.^[10],[11] Compounds with promising activity can be used as leads for synthesis of novel compounds with a high efficacy.^[12],[13] Potential lead candidates have been modified at β-position of flavanone ring against cancer which may act by inhibiting cell cycle and apoptosis pathway.^{[14],[15],[16],[17]} PI3K-Akt pathway in human with UniProtKB-ID: P31749^[15],[16] is used, and crystal structure of protein ID: 3CQW, which is available at Protein Data Bank (PDB), is used to study the docking interaction.^[18],[19]

Figure 1: Role of PI3K pathway in cell cycle arrest and apoptosis

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Figure 2: Flavanone (2-phenylchroman-4-one)

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Methodology

Sequence retrieval and analysis

PI3K-Akt sequences were selected from the UniProtKB ID: P31749. Crystal structures PDB ID: 3CQW were already solved and retrieved from the PDB database (www.rcsb.org) [Figure 3] PDBsum was used for cavity identification and generation of grid space for further docking procedures.

Figure 3: Active site pocket of 3cqw

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Compound library preparation and energy minimization

Flavanone [Figure 2] is the parent molecule, and modification of flavanone at β-position provides better stability and better pharmacokinetics and pharmacodynamics and enhances the stability of the compound. Lead library is prepared with the help of MarvinSketch software, and β-position is modified with knowledge-based approach by creating different substructures to get novel compounds. All designed molecules were validated, optimized, and docked with energy minimization algorithms using FlexX software^[14] (BIOVIA™ Scientific Innovation-Dassault Systèmes®biovia biosolve it USA) For further docking process, molecules were saved in structure data file and PDB format.

Results

Structural analysis and active site identification

PROMOTIF program was used for the detailed structural analysis of the crystal structure of Akt1 (PDB ID: 3CQW). The chain A contains 319 amino acids, three sheets, four beta-hairpin, five beta-bulges, nine strands, 16 helices, 16 helix–helix interactions, 24 beta-turn, and two gamma-turn active sites identified with PDBsum Ligplot. FlexX analyzes the local topological symmetry based on this conformation bonded and nonbonded parameters was calculated; it helps in detecting the proper bond distance angle and torsion potentials. It is one of the most accurate methods by providing flexibility to the ligand for receptor FlexX needs proper cavity information based on that it sets active site. Binding site can be defined with automated method or manuallyfor a co-crystallized ligand, we can set the coordinates anddefine the neighboring active site. By keeping the distance up to 6.5 A°–8 A° with the atoms of a known ligand at its crystalline position. In the overall calculations, FlexX also needs the information of solvent accessibility and intermolecular interactions

Molecular docking study

Flavanone derivatives of pharmacokinetics estimations performed with SwissADME and parameters are enlisted in [Table 1]. The binding modes of the flavanone and newly designed novel compounds are initially defined within the cavity of AKT1. Molecular docking studies were carried out with FlexX software with the implementation of genetic algorithms. By completing the final docking calculations of 100 molecules, best conformers were identified for their best binding energy which was observed from log file generated by the FlexX. Individual docking scores were calculated andbased on observation. Ten best docked molecule poses wereselected for AKT1, based on binding energy we have selected best three poses, which are common in AKT1 [Table 2] after performing the complete analysis and by calculating their bond distances and overall torsions. Thus based on observation, we have concluded that molecule number flavanone 29, flavanone 20, and flavanone 26 are more effective as compared to other flavanones, and also its binding affinity is more than the existing flavanone. These flavanone derivatives could become potential drug candidates against cancer. Best interaction poses are shown in [Figure 4] and [Figure 5].

Table 1: SwissADME predicted data along with interactions (pharmacokinetics/pharmacophore estimation)

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Table 2: Binding energy and interacting amino acid of best ligands with AKT1

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Figure 4: Interacting amino acid and pocket information of molecule 20

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Figure 5: Interacting amino acid and pocket information of molecule 29

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Discussion

The current research states the result of flavanone screening and identification of potent anti-cancerous against a key receptor, namely, AKT-1 which plays a major role in the overall processes of cell signaling and apoptosis pathway. After the overall filtering of flavanone derivatives from various drug databases such as DrugBank, Zinc, and PubChem database, we have identified 300 derivatives using the appropriate molecular property filter parameters. Additional flavanone derivatives are sketched with MarvinSketch software. Their molecular property filters such as SwissADME. Flavanone derivatives then docked with FlexX and the best 100 conformers were generated based on binding energy and by calculating bond angle distance flavanone molecules such as flavanone 29, flavanone 20, and flavanone 26 were ranked at top most novel compounds as compared to other flavanones against AKT-1 pathway.

Conclusion

The current studies show that novel flavanones derivatives would be used for the development of potent anti-cancer drugs acting by the inhibition of AKT-1 and may target different cell cycle pathways.

Acknowledgments

Authors are thankful to Dr. Debjani Dasgupta, Director, School of Biotechnology and Bioinformatics and D. Y. Patil University, CBD Belapur, Navi Mumbai. Authors extend their sincere thanks to Dr. D. Y. Patil Vidyapeeth, Pune, for the physical infrastructure and working space.

Financial support and sponsorship

Technical support by Dr. D. Y. Patil Vidyapeeth, Pune, India, and D. Y. Patil University, Navi Mumbai, Maharashtra, India.

Conflicts of interest

There are no conflicts of interest.

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