Browsing by Author "Chakma, Unesco"

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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
(PLOS, 2023-10-12) Akash, Shopnil; Aovi, Farjana Islam; Azad, Md. A. K.; Kumer, Ajoy; Chakma, Unesco; Islam, Md. Rezaul; Mukerjee, Nobendu; Rahman, Md. Mominur; Bayıl, Imren; Rashid, Summya; Sharma, Rohit
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. Furthermore, these molecules met the pharmacokinetics requirements for potential therapeutic candidates, displaying non-carcinogenicity, minimal aquatic and non-aquatic toxicity, and greater aqueous solubility. Collectively, our computational data suggest that Scutellarein derivatives may serve as potential therapeutic agents for TNBC. However, further experimental investigations are needed to validate these findings.
Chemical Descriptors, PASS, Molecular Docking, Molecular Dynamics and ADMET Predictions of Glucopyranoside Derivatives As Inhibitors to Bacteria and Fungi Growth
(Daffodil International University, 2022-04-02) Kawsar, Sarkar M. A.; Kumer, Ajoy; Munia, Nasrin S.; Hosen, Mohammed A.; Chakma, Unesco; Akash, Shopnil
The methyl α-D-glucopyranoside and its derivatives have been estimated as the antimicrobial agents against numerous human pathogens, which is constantly amplifying the attention of medicinal chemists to design new bioactive molecules and their structure-activity relationship (SAR) while the computational tools are the most lucid and trustable avenue to perform their theoretical profile building up. Firstly, the prediction of activity spectra for substances (PASS) value has illustrated initially information about the antifungal, antibacterial, antiviral, and anticancer potential. It was observed that the PASS predicted pathogens supported their score higher in fungal species than bacteria. However, the “Lipinski five rule” has been monitored for drug-likeness properties. After confirming their biological significance, molecular docking has been completed against both the bacteria and fungi and these docked complexes have been optimized for molecular dynamics through the water system. A molecular docking study against nine bacterial and fungal pathogens revealed promising binding affinity and non-bonding interaction mostly for derivatives (5-8). The chemical descriptors have been obtained using the density functional theory (DFT) and predict their chemical stability and softness in the biological system. The molecular dynamics study was found to be the best stability of all docked complexes. At last, the ADMET properties have been calculated and provide the safe use and non-carcinogenic fact with low toxicity for both aquatic and non-aquatic species. Finally, it is concluded that these selected derivatives (5-8) are highly antifungal potential molecules than antibacterial potential which has been varied with respect to their structural side chain in the D-glucopyranoside sequence.
Glucopyranoside Derivatives as Potential Antimicrobial Agents
(Trends in Carbohydrate Research, 2023-05-21) Islam, Sajia; Akash, Shopnil; Ferdous, Jannatul; Kumer, Ajoy; Al-Ghorbani, Mohammed; Baashen, Mohammed; Shbeer, Abdullah M.; Ageel, Mohammed; Chakma, Unesco; Hasan, Imtiaj; Rajia, Sultana; Fujii, Yuki; Ozeki, Yasuhiro; Kawsar, Sarkar M. A.
Methyl α-D-glucopyranoside and its seven acylated derivatives have been used to develop antibacterial and antifungal drugs by using in silico and in vitro antimicrobial functionality tests against five pathogenic bacteria and two fungi. Methyl α-D- glucopyranoside derivatives (1-8) were synthesized, purified, and characterized by physicochemical, elemental, and spectroscopic methods. Compounds 3 (zone of inhibition, 22±0.3 mm) and 8 (zone of inhibition, 24±0.4 mm) showed the highest inhibition against Bacillus subtilis and Staphylococcus aureus. A MIC value of 0.275±0.01 mg/ml was found for derivative 8 against S. ebony whereas the MBC value recorded for derivative 3 against S. aureus was 1.70±0.01 mg/ml. Most of these derivatives showed >78% inhibition of fungal mycelial growth. The in vitro effect of compound 8 against Ehrlich ascites carcinoma (EAC) cells, by MTT colorimetric assay, showed 25.97% of cell growth inhibition with an IC50 value of 1024.83 μg/ml. A DFT technique was used to determine the Highest Occupied Molecular Orbital (HOMO) and Lowest Unoccupied Molecular Orbital (LUMO), and the energy gap between them. Furthermore, the chemical reactivity and global descriptors were computed from the HOMO and LUMO values. The most crucial aspect of this research is the molecular docking against two gram-positive bacterial proteins (B. subtilis and S. aureus), two gram-negative bacterial proteins (Escherichia coli and Pseudomonas aeruginosa), and six fungal proteins (Aspergillus niger, Aspergillus flavus, Rhizomucor miehei, Mucor lusitanicus, Candida albicans and Candida Auris). In most cases, docking scores crossed the scores of the standard drugs, Azithromycin and Nystatin. A 100-ns molecular dynamics (MD) simulation study revealed stable conformation and binding patterns/energy in a stimulating environment. The range of quantitative structure-activity relationship (QSAR) and pIC50 found was between 4.19–9.15, signifying these compounds to be physiologically effective towards microbes. Most importantly, these compounds are non–carcinogenic, have low toxicity in aquatic and non–aquatic species, and are highly soluble in water and stable, indicating the suitability of these compounds as antimicrobial agents for therapeutic and drug development purposes.
Investigation of the New Inhibitors by Sulfadiazine and Modified Derivatives of α-D-glucopyranoside for White Spot Syndrome Virus Disease of Shrimp by In Silico
(Daffodil International University, 2022-06-08) Kumer, Ajoy; Chakma, Unesco; Rana, Md Masud; Chandro, Akhel; Akash, Shopnil; Elseehy, Mona M.; Albogami, Sarah; El-Shehawi, Ahmed M.
The α-D-glucopyranoside and its derivatives were as the cardinal investigation for developing an effective medication to treat the highest deadly white spot syndrome virus (WSSV) diseases in Shrimp. In our forthcoming work, both computational tools, such as molecular docking, quantum calculations, pharmaceutical kinetics, ADMET, and their molecular dynamics, as well as the experimental trial against WSSV, were executed to develop novel inhibitors. In the beginning, molecular docking was carried out to determine inhibitors of the four targeted proteins of WSSV (PDB ID: 2ED6, 2GJ2, 2GJI, and 2EDM), and to determine the binding energies and interactions of ligands and proteins after docking. The range of binding affinity was found to be between −5.40 and −7.00 kcal/mol for the protein 2DEM, from −5.10 to 6.90 kcal/mol for the protein 2GJ2, from −4.70 to −6.2 kcal/mol against 2GJI, and from −5.5 kcal/mol to −6.6 kcal/mol for the evolved protein 2ED6 whereas the L01 and L03 display the highest binding energy in the protein 2EDM. After that, the top-ranked compounds (L01, L02, L03, L04, and L05), based on their high binding energies, were tested for molecular dynamics (MD) simulations of 100 ns to verify the docking validation and stability of the docked complex by calculating the root mean square deviation (RMSD) and root mean square fluctuation (RMSF). The molecules with the highest binding energy were then picked and compared to the standard drugs that were been applied to fish experimentally to evaluate the treatment at various doses. Consequently, approximately 40–45% cure rate was obtained by applying the dose of oxytetracycline (OTC) 50% with vitamin C with the 10.0 g/kg feed for 10 days. These drugs (L09 to L12) have also been executed for molecular docking to compare with α-D-glucopyranoside and its derivatives (L01 to L08). Next, the evaluation of pharmacokinetic parameters, such as drug-likeness and Lipinski’s principles; absorption; distribution; metabolism; excretion; and toxicity (ADMET) factors, were employed gradually to further evaluate their suitability as inhibitors. It was discovered that all ligands (L01 to L12) were devoid of hepatotoxicity, and the AMES toxicity excluded L05. Additionally, all of the compounds convey a significant aqueous solubility and cannot permeate the blood-brain barrier. Moreover, quantum calculations based on density functional theory (DFT) provide the most solid evidence and testimony regarding their chemical stability, chemical reactivity, biological relevance, reactive nature and specific part of reactivity. The computational and virtual screenings for in silico study reveals that these chosen compounds (L01 to L08) have conducted the inhibitory effect to convey as a possible medication against the WSSV than existing drugs (L09, L10, L11 and L12) in the market. Next the drugs (L09, L10, L11 and L12) have been used in trials.
Mechanistic Inhibition of Monkeypox and Marburg Virus Infection by O-Rhamnosides and Kaempferol-O-Rhamnosides Derivatives
(Frontier Scientific Publishing, 2023-05-24) Mashud, Md Abdullah Al; Kumer, Ajoy; Mukerjee, Nobendu; Chandro, Akhel; Maitra, Swastika; Chakma, Unesco; Dey, Abhijit; Akash, Shopnil; Alexiou, Athanasiosis; Khan, Azmat Ali; Alanazi, Amer M; Ghosh, Arabinda; Chen, Kow-Tong; Sharma, Rohit
"The increasing incidence of Monkeypox virus (Mpox) and Marburg virus (MARV) infections worldwide presents a significant challenge to global health, as limited treatment options are currently available. This study investigates the potential of several O-rhamnosides and Kaempferol-O-rhamnosides as Mpox and MARV inhibitors using molecular modeling methods, including ADMET, molecular docking, and molecular dynamics/MD simulation. The effectiveness of these compounds against the viruses was assessed using the Prediction of Activity Spectra for Substances (PASS) prediction. The study's primary focus is molecular docking prediction, which demonstrated that ligands (L07, L08, and L09) bind to Mpox (PDB ID: 4QWO) and MARV (PDB ID: 4OR8) with binding affinities ranging from -8.00 kcal/mol to -9.5 kcal/mol. HOMO-LUMO based quantum calculations were employed to determine the HOMO-LUMO gap of frontier molecular orbitals (FMOs) and to estimate chemical potential, electronegativity, hardness, and softness. Drug similarity and ADMET prediction assessments of pharmacokinetic properties revealed that the compounds were likely non-carcinogenic, non-hepatotoxic, and rapidly soluble. Molecular dynamic (MD) modeling was used to identify the most favorable docked complexes involving bioactive chemicals. MD simulations indicate that varying types of kaempferol-O-rhamnoside are necessary for successful docking validation and maintaining the stability of the docked complex. These findings could facilitate the discovery of novel therapeutic agents for treating illnesses caused by the Mpox and MARV viruses."
Modified D-Glucofuranose Computationally Screening for Inhibitor of Breast Cancer and Triple Breast Cancer: Chemical Descriptor, Molecular Docking, Molecular Dynamics and Qsar
(Daffodil International University, 22-09-02) Kumer, Ajoy; Chakma, Unesco; Chandro, Akhel; Howlader, Debashis; Akash, Shopnil; Hossain, Tomal; Kobir, MD. Eleas; Matin, Mohammed M.
Drug discovery and the process of new drug design have been formulated much easier in the past two decades by introducing and proliferation of combined physical and biochemical process from computing capabilities and computational approaches. Since the breast cancer is one of the life-threatening problems globally, and no effective prescription is still now invented or not available in the market or medical treatment. Although few is just touched on the market, but the remedy has consisted of severe side effects and low efficiency. Regarding that fact, the D-Glucofuranose and its derivative have been designed by the quantum calculation, molecular docking, ADMET and SAR analysis. For molecular docking, the cancer protease (3hb5) and triple-negative breast cancer protease (4pv5) are selected whereas the binding affinity is at ranging from -6.20 to -10.40 kcal/mol, and it is slightly lower than cancer protease (3hb5) for triple-negative breast cancer protease (4pv5). Our comprehensive study has shown that 03, 05, and 08 could be considered the potential drug comparison with standard. These three drugs completed all the criteria, including high binding energy, non-toxic, non-carcinogenic, and highly soluble in biological system.
Quantum Calculation, Docking, ADMET and Molecular Dynamics of Ketal and Non-ketal Forms of D- glucofuranose Against Bacteria, Black & White Fungus, and Triple-Negative Breast Cancer
(Biointerface Research in Applied Chemistry, 2023) Akash, Shopnil; Kumer, Ajoy; Chandro, Akhel; Chakma, Unesco; Matin, Mohammed Mahbubul
"D-glucofuranose has potent bioactivity against numerous diseases and pathogens, such as bacteria, fungi, viruses, and cancer. Normally, the ketal form of D-glucofuranose is converted into the non-ketal form by drug metabolism in the human body; as a result, both the ketal and non-ketal forms of D-glucofuranose are considered. To make a comparative biological activity study of ketal and nonketal species of nine derivatives of D-glucofuranose, two bacteria, black fungus, white fungus, and triple-negative breast cancer, were selected. Firstly, the PASS prediction data from the online PASS tool indicated the probability of pathogenic efficacy through the Pa and Pi parameters. Secondly, the computational studies, such as molecular docking, molecular dynamic, ADMET, drug-likeness, pharmacokinetic, aquatic, and non-aquatic features, were calculated with three FDA-approved drugs, including azithromycin, nystatin, and cyclophosphamide. A comparative study of computational data has been performed where the ketal forms of D-glucofuranose derivatives were found highly biologically active with the satisfaction of the pharmacokinetic parameters, ADMET parameters, and Lipinski rule."
Rhamnopyranoside Pivaloyl Esters as Black and White Fungus Inhibitors: Molecular Docking, Dynamics and Admet Analysis
(Federal University of Mato Grosso do Sul, 2024-06-04) Matin, Mohammed M.; Kumer, Ajoy; Chandro, Akhel; Akash, Shopnil; Chakma, Unesco
The "Black and White Fungus" is a very infrequently developing pathogen with a high fatality rate that has prompted widespread public health concern during the period of the COVID-19 pandemic. This pathogenic fungus may be widely distributed in nature, in plants, and in deteriorating fruits and vegetables because of its widespread nature. Numerous sugar molecules, such as glucopyranoside and glucofuranose, have been reported to have significant antibacterial, antifungal, and antiviral activity, and they were also revealed to be able to inhibit multidrug-resistant microorganisms. The recent black fungus epidemic was extremely serious in India, combined with COVID-19, which contributed to the high mortality impact and deterioration of the situation due to the unavailability of effective treatments. So, rhamnopyranose type derivatives 1–9 were studied against the proteins associated with black and white fungi such as Mycolicibacterium smegmatis (PDB ID 7D6X), Rhizomucor miehei (PDB ID 4WTP), Candida auris (PDB ID 6U8J), and Aspergillus luchuensis (PDB 1BK1). These compounds exhibited favorable physical and biochemical scores, as well as appropriate ADMET metrics, among other characteristics. Following the molecular docking procedure, it was found that 1–9 had the highest binding affinity in most cases, (> -6.00 kcal/mol), while compound 9 had outstanding binding affinity against Rhizomucor miehei (-8.7 kcal/mol) and against Mycolicibacterium smegmatis (-8.2 kcal/mol). In addition, the binding affinity against white fungus is also outstanding. This time, compounds 8 and 9 had better binding energy, which is -7.8 kcal/mol against Aspergillus luchuensis (1BK1) and -7.6 kcal/mol against Candida auris (6U8J). Finally, the molecular dynamics simulation at 100 ns has proved that they are stable for new medication development. Among the derivatives 1–9, ligands 8 and 9 exhibited potential medicinal characteristics when all of the data were considered.