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ISSN: 2637-4706

Drug Designing & Intellectual Properties International Journal

Research Article(ISSN: 2637-4706)

Identification of Sirtuin Drug Targets (Homosapiens) For Lung Cancer-Molecular Docking and ADME Analysis Volume 3 - Issue 4

Sameer* and Sudhakar Malla

  • Department of Biotechnology, Indian Academy Degree College, Bangalore

Received: April 25, 2020;   Published: May 20, 2020

Corresponding author: Sameer, Department of Biotechnology, Indian Academy Degree College, Bangalore

DOI: 10.32474/DDIPIJ.2020.03.000168

Abstract PDF


The objective of this study was to investigate the specific drug targets (Sirtuin 1,2,3,4,5, and 6) for lung cancer employing molecular docking simulation and ADME analysis against Sinapaldehyde. The three-dimensional structure of the protein was retrieved from Protein Data Base and of the ligand from Pubchem database. Molecular docking simulation of the compounds was performed using Ligpep 2.3, Schrodinger Suite 2009. In the present study, drug likeness analysis was performed through Lipinski filter & Admesar analysis using Swissadme online server and none of the compounds breached Lipinski’s and ADME parameters, making them prominent agents for bio-activities. And the outcome represents the compounds (Sinapaldehyde) possibly serve as for the cure of lung cancer.

Keywords: Sirtuin; Sinapaldehyde; Molecular docking; Lipinski; ADME analysis, Anti-cancer


Lung cancer is the prominent source of cancer associated death across the world with a survival rate of 20% [1]. Lung cancer can be differentiated into small cell lung cancer and non-small cell lung cancer [2]. In the earlier decades, a huge number of metabolic pathways like EGFR (Epidermal Growth Factor Receptor) signaling pathway have been observed in the carcinogenesis family indulging lung cancer & are used as specific targets in drug development [3,4]. Sirtuins are group of proteins homologous to yeast regulator (Sir 2) that was identified in 1984 as a gene obligatory for continuing silent chromatin in yeast [5]. Sirtuins family of proteins also came out to play a major role in various pathological & physiological processes. Sirtuins genes (SIRT1-7), in mammals [6,7]. Sirtuins genes are basically classes of proteins which acquire nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase (SIRT1, SIRT2, SIRT3, SIRT5, SIRT6, and SIRT7) and monoribosytransferase (SIRT4, and SIRT6) activities [8-15]. Except SIRT5, all mammalians Sirtuins have been noted to be indulged in cancer development but the roles of Sirtuins proteins in cancer are very complex and attribute to cancer cells promotion or suppression [16]. The selected ligand was recognized for prediction against novel targets and predicted to interact with Sinapaldehyde also called (E)-3-(4-hydroxy- 3,5-dimethoxyphenyl)-2-propenal, representative of the class of compounds called as methoxyphenols which are water-insoluble and a very weak compound (Table 1). (acidic in nature). During lignin biosynthesis in Arabidopsis thaliana, an enzyme called dihydroflavonol-4-reductase utilizes NADPH & Sinapaldehyde to generate sinapyl alcohol & NADP+ (Figure 1). In the present study, comparative investigation of the specific human sirtuin proteins was carried out using molecular docking techniques which identified the drug likeness of the respective ligand.

Figure 1: Sinapaldehyde.


Table 1: Activities and Functions of Target Human sirtuin proteins.



Active binding site

The 3D structure of sirtuin (1, 2, 3, 4, 5, and 6) proteins (PDBID: 4kxq.1.B, 1j8f.1.A, 4bn5.1.A, 5oj7.1.A, 5bwl.1.A, 3pki.1.A) was build using SWISS-MODEL. Recognition of protein binding sites were identified by FT site server and Pro-Bis server [17]. Recognition of binding site has a broad range of pertinences which indulges functional relationships between proteins, structure-based prediction, and drug design. And FT site server also exposed a specific method for protein binding identification [18].

Ligand formation

Ligands are tiny molecules which bind to the Protein’s binding sites. Sinapaldehyde structure obtained from Pubchem database [19]. The compounds were converted to three-dimensional structure with the help of PyMol version 1.3 [20]. And physicchemical properties of the ligands are measured by Pubchem database.

Study of drug likeness of ligands

Lipinski filter were used for ligand prediction, according to drug likeness criteria namely cLogP, hydrogen donor and acceptor, molecular mass & molar refractive index [21]. SWISS-ADME was used as convenient tool in drug investigation [22] and ligand properties with respect to adsorption, distribution, metabolism, and excretion (ADME). BOILED-EGG (Brain or Intestinal Estimated permeation method) is approached as an accurate model that works properly by computing the polarity of tiny molecules [23].

Molecular docking simulation

Figure 2: Cartoon representation of Sirtuin proteins (1, 2,3,4,5, and 6).


The purpose of molecular docking is to assume or predict the binding aspects of ligand and identify the orientation of molecule with respect to active site. In docking method, all the binding poses of molecules innards the catalytic site of an enzyme is being concluded. After that, preparation of protein of the specific target sirtuin proteins 1,2,3,4,5,and 6 (PDB ID: 4kxq.1.B, 1j8f.1.A, 4bn5.1.A, 5oj7.1.A, 5bwl.1.A, 3pki.1.A) was performed with employing Protein preparation wizard of Schrodinger 09 in which missing hydrogen bond were assigned subjected by energy minimization (Figure 2-4).

Figure 3: Active sites in selected sirtuin proteins 1, 2,3,4,5, and 6.


Figure 4: 3D structure of Sinapaldehyde.


The receptor network was groomed keeping ligand (Sinapaldehyde) at the centre of framework with 20A edges bearing catalytic site. Primarily docking simulation on the cocrystal was groomed on prepared receptor for cross validating the binding ability with subject to X-ray crystal structure binding mode. Moreover, molecular docking method was implemented against PDB ID employing Glide XP 5.8 [24-26]. and top analogs on docking score as well as binding synergy with catalytic fragments were allowed for induced fit docking and outcomes were compared after Glide XP. The lowest energy suggested by Glide program was noted as the most probable binding pose of top compound (Table 2).

Table 2: Physico-chemical properties of the ligand.


Results and Discussion

Active binding sites of protein molecule

In this study, FT site server was used to predict the active sites of the targeted proteins (sirtuin 1, 2,3,4,5, and 6).


Drug likeness analysis

Lipinski filter analysis was used to explain the rigidity of all compounds to be considered for structure-based drug design (Table 3-5).

Table 3: Lipinski Filter Analysis.


Table 4:Adamesar Analysis.


Table 5:Molecular docking results against Sinapaldehyde (ligand).


Molecular docking simulation

According to molecular docking simulation, results observed from induced fit docking of compounds at the binding site of sirtuin proteins showed better docking score than the already known drugs for anticancer which predicts that the compounds have the better binding affinity to the receptors. The molecular docking result showed good binding affinity in all specific targeted proteins (Figure 5,6).

Figure 5: Physico-chemical space of molecules with highest probability of being utilized by the GI tract shown in white region, whereas the yellow region shown the physic-chemical space of molecules with highest probability to penetrate the brain.


Figure 6: Molecular docking simulation of sirtuin proteins (1, 2, 3, 4, 5, and 6) with ligand namely Sinapaldehyde. The docking results showed that all selected compounds for docking exposed an excellent binding affinity. SIRT2 showed highest glide energy (-81.7) followed by SIRT5 (-79.2).



In silico studies of the selected sirtuin proteins (1,2,3,4,5, and 6) showed the favorable result against ligand namely Sinapaldehyde. The selected compounds exposed better outcomes in silico analysis and characterization with good efficiency in aspects of docking score and glide energy. According to ADME predictions, Gastrointestinal absorption is very high and absence of permeability glycoprotein substrate. Hence, it has assumed or predicted that the compound (Sinapaldehyde) possibly serve as for the treatment of lung cancer and might be in future be utilized in in vivo studies to predict their effects on the abilities for the cure of cancer.


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