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A Drug Design Strategy Based on Molecular Docking and Molecular Dynamics Simulations Applied to Development of Inhibitor Against Triple-negative Breast Cancer by Scutellarein Derivatives

Shopnil Akash, Farjana Islam Aovi, Md. A. K. Azad, Ajoy Kumar, Unesco Chakma, Md. Rezaul Islam, Nobendu Mukerjee, Md. Mominur Rahman, Imren Bayil, Summya Rashid, Rohit Sharma


Triple-negative breast cancer (TNBC), accounting for 10–15% of all breast malignancies, is more prevalent in women under 40, particularly in those of African descent or carrying the BRCA1 mutation. TNBC is characterized by the absence of estrogen and progesterone receptors (ER, PR) and low or elevated HER2 expression. It represents a particularly aggressive form of breast cancer with limited therapeutic options and a poorer prognosis. In our study, we utilized the protein of TNBC collected from the Protein Data Bank (PDB) with the most stable configuration. We selected Scutellarein, a bioactive molecule renowned for its anti-cancer properties, and used its derivatives to design potential anti-cancer drugs employing computational tools. We applied and modified structural activity relationship methods to these derivatives and evaluated the probability of active (Pa) and inactive (Pi) outcomes using pass prediction scores. Furthermore, we employed in-silico approaches such as the assessment of absorption, distribution, metabolism, excretion, and toxicity (ADMET) parameters, and quantum calculations through density functional theory (DFT). Within the DFT calculations, we analyzed Frontier Molecular Orbitals, specifically the Highest Occupied Molecular Orbital (HOMO) and Lowest Unoccupied Molecular Orbital (LUMO). We then conducted molecular docking and dynamics against TNBC to ascertain binding affinity and stability. Our findings indicated that Scutellarein derivatives, specifically DM03 with a binding energy of -10.7 kcal/mol and DM04 with -11.0 kcal/mol, exhibited the maximum binding tendency against Human CK2 alpha kinase (PDB ID 7L1X). Molecular dynamic simulations were performed for 100 ns, and stability was assessed using root-mean-square deviation (RMSD) and root-mean-square fluctuation (RMSF) parameters, suggesting significant stability for our chosen compounds. 


Breast cancer is a difficult challenge for the global public health community and the disease’s growing prevalence [1]. It seems to substantially affect the lives of a large number of females globally by breast cancer [2, 3]. Among different types of breast cancer, triple-negative breast cancer (TNBC), one of the breast cancer subtypes with negative expression of progesterone receptor (PR), estrogen receptor (ER), and human epidermal growth factor receptor-2 (HER2), spread quickly to other body regions which has a higher chance of early decline and death than other subtypes of cancer [4]. Approximately one million women are diagnosed with breast cancer annually, and TNBC accounts for approximately 15–20 percent [5, 6]. According to epidemiological research findings, TNBC is most often diagnosed in young premenopausal women under the age of 40. These makeup around 15–20% of all breast cancer patients [7]. The survival duration for TNBC is lower than those diagnosed with other breast cancer subtypes. Forty percent of fatalities are during the first five years following identification [8, 9]. TNBC is resistant to endocrine therapy and other molecular therapeutic strategies due to the distinct genetic phenotype that makes it susceptible to these treatments [10].

Materials and methodology

2.1 Ligand preparation and optimization

For the preparation of ligands, all the chemical structures of Scutellarein derivatives have been designed by ChemBioDraw 12.0 [28]. Then, these Scutellarein derivatives were uploaded in material studio and optimize through the implementation of the DFT (density functional theory) from the DMol3 code [29–31]. The B3LYP functional and DNP basis sets were implemented in DMol3 code to get such exact outcomes [32]. These analytical tools were implemented to establish the frontier molecular orbitals (HOMO, LUMO) and the amplitude of the HOMO and LUMO following optimization. The optimized molecules were exported as PDB file types in order to be used for subsequent computer work, such as molecular docking, molecular dynamic, and ADMET. The magnitude of chemical reactivity and characteristics are approximated by applying relevant and approved algorithms, and the results are listed in Table 4. the energy gap; hardness; softness was calculated for the reported drug candidate.


Designing derivatives of Scutellarin

The primary compound was Scutellarin which has previously been documented as anti-cancer, antimicrobial, and many more pharmacological effects [49, 50]. So, based on the previous investigation and literature review, the Scutellarein structure has been modified to predict the potential anti-cancer efficiency against targeted TNBC. Since the structure-activity relationship is a well-known approach for developing and designing new and innovative molecules to assist in the discovery or synthesis of a novel drug to get desired qualities and activities. The different position of the functional group of Scutellarein has been substituted by the Benzene ring, OCH3, & NH-CH2-CH2-OH to obtain better efficacy and potential drug for inhibiting TNBC. The main objective is to identify how different functional groups impact pharmacological activity on Scutellarein against TNBC. The modified chemical structures of TNBC are shown in Fig 3.


Aquatic and non-aquatic toxicity

Another parameter is aquatic and non-aquatic toxicity. Aquatic and non-aquatic toxicity is a significant objective in assessing undesirable impacts on the environment or human use [75]. In this investigation, a series of computational methods for evaluating biochemical aquatic and non-aquatic toxicity have been discussed with different parameters such as AMES toxicity, oral rat acute toxicity (LD50), oral rat chronic toxicity, etc. In this case, it has been proven that all the drugs are free from AMES toxicity without DM02. The maximum tolerated dose for a human is 0.781 mg/kg/day in DM01. At the same time, the lowest maximum tolerated dose is 0.358 mg/kg/day in Ligand DM09, which indicates that the highest dose of 0.781 mg/kg/day should be taken for a given period (24 Hours); otherwise, the adverse effect may produce. According to current estimates, the acute oral toxicity and the oral rat chronic toxicity of the active compounds vary, with values ranging from 2.418 mg/kg/day to 3.43 mg/kg/day being documented for the oral rat acute toxicity, where the oral rat chronic toxicity being reported from -0.086 mg/kg/day to 4.029 mg/kg/day. Finally, they all are free from skin sensitization with the lowest T. pyriformis toxicity. So, it can be concluded that they might have no adverse effect on aquatic and non-aquatic and could be performed further experimental works in laboratories.


Our computational analysis aimed to determine the potential therapeutic impact of Scutellarin derivatives against Triple-Negative Breast Cancer (TNBC) and to assess the influence of different functional group additions on binding affinity. The outcomes of this investigation suggest promising efficacy of novel Scutellarin derivatives against TNBC. As highlighted earlier, the Prediction of Activity Spectra for Substances (PASS) results we acquired for our compounds demonstrated a stronger antineoplastic activity than antiviral, antifungal, and antibacterial activities. This led us to focus predominantly on TNBC. For TNBC (PDB ID 7L1X), the docked compounds of modified molecules displayed high binding affinities and remarkable non-bonding interactions (DM03–10.7 kcal/mol, DM04–11.0 kcal/mol, with the most substantial binding affinity observed at -10.5 against (PDB ID 5HA9) for ligand DM02 and ligand DM05). The calculated maximum softness values of the drugs have been reported as 1.1608, suggesting their rapid metabolism upon entering the body. Modified Scutellarin derivatives, such as capecitabine, are projected to have higher reactivity than traditional ligands due to their smaller HOMO-LUMO energy gaps. From an ADMET perspective, the theoretical findings suggested that the new Scutellarin derivatives are safer than reference drugs in terms of toxicity, water solubility, distribution volume, and clearance rate. Importantly, they showed no carcinogenic effects, except for ligand DM02. The improved ADMET properties of Scutellarin derivatives compare favorably with gold-standard drugs, highlighting their potential as a safer treatment alternative. 


Author would like to acknowledge Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Daffodil Smart City, Birulia, Savar, Dhaka-1216, Bangladesh.

Citation: Akash S, Aovi FI, Azad MAK, Kumer A, Chakma U, Islam MR, et al. (2023) A drug design strategy based on molecular docking and molecular dynamics simulations applied to development of inhibitor against triple-negative breast cancer by Scutellarein derivatives. PLoS ONE 18(10): e0283271.

Editor: Sheikh Arslan Sehgal, The Islamia University of Bahawalpur Pakistan, PAKISTAN

Received: March 4, 2023; Accepted: May 7, 2023; Published: October 12, 2023

Copyright: © 2023 Akash et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are given within the paper.

Funding: The authors received no specific funding for this work.

Competing interests: The authors have declared that no competing interests exist.

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