Chemistry and Biodiversity

Natural Flavonoids as Primary Amoebic MeningoencephalitisInhibitor: Virtual Screening, Molecular Docking, MD Simulation, MMPBSA, Density Functional Theory, Principal Component, and Gibbs Free Energy Landscape Analyses.

Publication typeJournal Article
Publication date2024-12-03
scimago Q2
wos Q3
SJR0.405
CiteScore3.4
Impact factor2.3
ISSN16121872, 16121880
Abstract
ABSTRACT

Flavonoids have been showing diversified bioactivities. Primary amoebic meningoencephalitis is a brain inflammation caused by Naegleria fowleri brain eating amoeba. In this manuscript, we selected 93 flavonoids by extensive literature survey and 83 flavonoids passed drug likeness parameter. Selected flavonoids were molecular docked against primary amoebic meningoencephalitis N. fowleri CYP51 receptor considering voriconazole as standard. Beta naphthoflavone, abyssinone I, and abyssinone III showed maximum docking scores of −10.9 kcal/mol, −10.7 kcal/mol, and −10.6 kcal/mol, respectively, whereas voriconazole showed docking scores of −7.6 kcal/mol. Molecular dynamic simulation data showed that RMSD values attained almost a static value during the simulation, and all nearest interacting amino acid residues were fluctuated within limit. Molecular Mechanics Poisson‐Boltzmann Surface Area (MMPBSA) data of beta naphthoflavone abyssinone I, abyssinone III, and voriconazole showed free binding energies of −82.755 kJ/mol, −1924.193 kJ/mol, −1890.335 kJ/mol, and −540.141 kJ/mol, respectively. Frontier molecular orbital (FMO) analysis showed that abyssinone III was the chemically reactive molecule and beta naphthoflavone showed maximum electrophilicity. Molecular electrostatic potential (MEP) analysis portrayed possible nucleophilic‐electrophilic attack areas of the structures. PCA and free energy landscape (FEL) analysis data confirmed the stable conformations between flavonoids and receptor. Abyssinone I and III showed nontoxic behavior. These data confirmed that if we repurpose these flavonoids against primary amoebic meningoencephalitis, it will be beneficial for mankind.

Akter N., Saha S., Hossain M.A., Uddin K.M., Bhat A.R., Ahmed S., Kawsar S.M.
Chemical Physics Impact scimago Q2 wos Q2 Open Access
2024-12-01 citations by CoLab: 4 Abstract  
Carbohydrates, among the most abundant and widespread biomolecules in nature, play indispensable roles in diverse biological functions and represent a treasure trove of untapped potential for pharmaceutical applications. From this perspective, the present study was designed to explore and evaluate the synthesis and spectral characterization of methyl α-D-glucopyranoside derivatives 2-6 with different aliphatic groups through comprehensive in vitro antimicrobial screening, physicochemical analysis, molecular docking and molecular dynamics analysis, and pharmacokinetic prediction. The unimolar one-step propionylation of methyl α-D-glucopyranoside under controlled conditions furnished 6-O-propionyl derivative 2 and the development of glucoopyranoside-based potential antimicrobial derivatives, which were further converted into four newer 2,3,4-tri-O-glucopyranoside derivatives (3-6) in reasonably good yields. The chemical structures of the newly synthesized analogs were ascertained by analyzing their physicochemical, elemental, FTIR, and NMR spectroscopic data. In vitro antimicrobial tests against five bacteria and two fungi indicated the promising antibacterial functionality of these synthesized analogs compared with their antifungal activity. Structure-activity relationship (SAR) analysis indicated that adding lauroyl> stearoyl > palmitoyl groups to the ribose moiety increased the potency against bacterial and fungal strains. In support of this observation, molecular docking experiments were performed on the 3TI6 H1N1 receptor and the 6VMZ H5N1 receptor. Molecular interactions with solvents were investigated in terms of FMO, HOMO-LUMO, and MEP properties. In addition, a 100 ns molecular dynamics simulation process was performed to monitor the behavior of the complex structure formed by the receptor 6VMZ under in silico physiological conditions to examine its stability over time, which revealed a stable conformation and binding pattern in a stimulating environment of methyl α-D-glucopyranoside derivatives. Pharmacokinetic predictions were investigated to evaluate their absorption, distribution, metabolism and toxic properties, and the combination of pharmacokinetic and drug-likeness predictions has shown promising results in silico.
Wei C., Zhang H., Niu L., Zhong Q., Yan H., Wang J.
2024-10-01 citations by CoLab: 2 Abstract  
Human glutaminyl cyclase (hQC) inhibitors have great potential to be used as anti- Alzheimer's disease (AD) agents by reducing the toxic pyroform of β-amyloid in the brains of AD patients. The four-dimensional quantitative structure activity relationship (4D-QSAR) model of N-substituted urea/thioureas was established with satisfying predictive ability and statistical reliability (Q
Alharbi A.S., Altwaim S.A., El-Daly M.M., Hassan A.M., AL-Zahrani I.A., Bajrai L.H., Alsaady I.M., Dwivedi V.D., Azhar E.I.
BMC Chemistry scimago Q2 wos Q2 Open Access
2024-07-30 citations by CoLab: 3 PDF Abstract  
The escalating threat posed by the Monkeypox virus (MPXV) to global health necessitates the urgent discovery of effective antiviral agents, as there are currently no specific drugs available for its treatment, and existing inhibitors are hindered by toxicity and poor pharmacokinetic profiles. This study aimed to identify potent MPXV inhibitors by screening a diverse library of small molecule compounds derived from marine fungi, focusing on the viral protein VP39, a key methyltransferase involved in viral replication. An extensive virtual screening process identified four promising compounds—CMNPD15724, CMNPD28811, CMNPD30883, and CMNPD18569—alongside a control molecule. Rigorous evaluations, including re-docking, molecular dynamics (MD) simulations, and hydrogen bond analysis, were conducted to assess their inhibitory potential against MPXV VP39. CMNPD15724 and CMNPD30883, in particular, demonstrated a superior binding affinity and stable interactions within the target protein's active site throughout the MD simulations, suggesting a capacity to overcome the limitations associated with sinefungin. The stability of these VP39-compound complexes, corroborated by MD simulations, provided crucial insights into the dynamic behavior of these interactions. Furthermore, Principal Component Analysis (PCA) based free energy landscape assessments offered a detailed understanding of the dynamic conformational changes and energetic profiles underlying these compounds' functional disruption of VP39. These findings establish CMNPD15724, CMNPD28811, CMNPD30883, and CMNPD18569 as promising MPXV inhibitors and highlight marine fungi as a valuable source of novel antiviral agents. These compounds represent potential candidates for further experimental validation, advancing the development of safer and more effective therapeutic options to combat this emerging viral infection.
SHAH U., Patel N., Patel M., Rohit S., Solanki N., Patel A., Patel S., Patel V., Patel R., Jawarkar R.D.
Chemistry and Biodiversity scimago Q2 wos Q3
2024-05-20 citations by CoLab: 3 Abstract  
AbstractBreast cancer is a global health concern, demanding innovative treatments. Targeting the Transforming Growth Factor‐beta (TGF‐β) signaling pathway, pivotal in breast cancer, is a promising approach. TGF‐β inhibits proliferation via G1 phase cell cycle arrest, acting as a suppressor initially, but in later stages, it promotes progression by enhancing motility, invasiveness, and metastasis formation. This study explores naturally occurring flavonoids′ interactions with TGF‐β. Using molecular docking against the protein‘s crystal structure (PDB Id: 1PY5), Gossypin showed the highest docking score and underwent molecular dynamics simulation, revealing complex flexibility and explaining how flavonoids impede TGF‐β signaling in breast cancer. ADMET predictions adhered to Lipinski's rule of Five. Insights into flavonoid‐TGF‐β binding offer a novel angle for breast cancer treatment. Flavonoids having a good docking score like gossypin, morin, luteolin and taxifolin shown potent cytotoxic effect on breast cancer cell line, MCF‐7. Understanding these interactions could inspire flavonoid‐based therapies targeting TGF‐β to halt breast cancer growth. These findings pave the way for personalized, targeted breast cancer therapies, offering hope against this formidable disease.
Kawsar S.M., Hossain M.A., Saha S., Abdallah E.M., Bhat A.R., Ahmed S., Jamalis J., Ozeki Y.
ChemistrySelect scimago Q3 wos Q3
2024-04-15 citations by CoLab: 13 Abstract  
AbstractThis review article aims to significantly advance the scientific community's efforts to develop effective nucleoside‐based drugs for treating severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and other emerging infectious diseases. This study concentrates on the main viral protease (Mpro) and explores nucleoside‐based compounds as potential therapeutic agents. This investigation investigated the impact of acylation‐induced modifications on the nucleoside hydroxyl group and subsequent properties. Nucleoside analogs, which are recognized for their diverse biochemical properties, were synthesized and rigorously screened to evaluate their antimicrobial efficacy. In the domain of pharmaceutical research, computational pharmacokinetics has emerged as a critical tool, especially in the pursuit of nucleoside analogs as potential therapeutics. In silico methods aid in predicting pharmacokinetic traits, interactions with crucial enzymes, and the stability of these analogs in biological environments, thereby streamlining drug design and reducing experimental costs. Concurrently, computational studies revealed the intricate interactions between the analogs and the active site of the main protease. The amalgamation of experimental screening and computational insights underscores the emergence of potent nucleoside candidates with inhibitory activity against SARS‐CoV‐2 Mpro. Additionally, this review integrates computational studies that provide valuable insights into the interactions between nucleoside analogs and the main protease of SARS‐CoV‐2.
Shah A., Choudhary A., Jain M., Perumal S., Patel V., Parmar G., Patel A.
3 Biotech scimago Q2 wos Q3
2024-02-18 citations by CoLab: 15 Abstract  
Virtual screening of a library of 329 flavonoids obtained from the NPACT database was performed to find out potential novel HDAC2 inhibitors. Eleven out of 329 selected flavonoids were screened based on molecular docking studies, as they have higher binding affinities than the standard drugs vorinostat and panobinostat. All screened compounds occupying the catalytic site of HDAC2 showed important molecular interaction with Zn2+ and other important amino acids in the binding pocket. The screened compounds were validated using ADMET filtration and bioactivity prediction from which we obtained six compounds, NPACT00270, NPACT00676, NPACT00700, NPACT001008, NPACT001054, and NPACT001407, which were analyzed using DFT studies. DFT studies were performed for all six screened flavonoids. In DFT studies, three flavonoids, NPACT00700, NPACT001008, and NPACT001407, were found to be better based on HOMO–LUMO and molecular electrostatic potential (MEP) analyses. Furthermore, MD simulations were performed for 100 ns for the three compounds. In the MD analysis, NPACT001407 was found to be more stable in the active site of HDAC2 as zinc formed a coordination bond with ASP181, HIS183, ASP269, and GLY305, along with two hydroxyl groups of the ligand. Our findings reveal that these flavonoids can interact as ligands with the active site of HDAC2. Because of the absence of a hydroxamate group in flavonoids, there are no possibilities for the formation of isocyanate. This suggests that the major drawback of current HDACs inhibitors may be solved. Further experimental validation is needed to understand the selectivity of flavonoids as HDAC2 inhibitors.
Akter S., Alhatlani B.Y., Abdallah E.M., Saha S., Ferdous J., Hossain M.E., Ali F., Kawsar S.M.
Molecules scimago Q1 wos Q2 Open Access
2023-12-07 citations by CoLab: 10 PDF Abstract  
The pursuit of innovative combinations for the development of novel antimicrobial and antiviral medications has garnered worldwide interest among scientists in recent times. Monosaccharides and their glycosides, such as methyl α-d-mannopyranoside derivatives, play a significant role in the potential treatment of viral respiratory pathologies. This study was undertaken to investigate and assess the synthesis and spectral characterization of methyl α-d-mannopyranoside derivatives 2–6, incorporating various aliphatic and aromatic groups. The investigation encompassed comprehensive in vitro antimicrobial screening, examination of physicochemical properties, molecular docking analysis, molecular dynamics simulations, and pharmacokinetic predictions. A unimolar one-step cinnamoylation reaction was employed under controlled conditions to produce methyl 6-O-cinnamoyl-α-d-mannopyranoside 2, demonstrating selectivity at the C-6 position. This represented a pivotal step in the development of potential antimicrobial derivatives based on methyl α-d-mannopyranoside. Subsequently, four additional methyl 6-O-cinnamoyl-α-d-mannopyranoside derivatives were synthesized with reasonably high yields. The chemical structures of these novel analogs were confirmed through a thorough analysis of their physicochemical properties, elemental composition, and spectroscopic data. In vitro antimicrobial assays were conducted against six bacterial strains and two fungal strains, revealing promising antifungal properties of these methyl α-d-mannopyranoside derivatives in comparison to their antibacterial activity. Moreover, cytotoxicity testing revealed that the compounds are less toxic. Further supporting these findings, molecular docking studies were performed against the H5N1 influenza A virus, indicating significant binding affinities and nonbonding interactions with the target protein 6VMZ. Notably, compounds 4 (−7.2) and 6 (−7.0) exhibited the highest binding affinities. Additionally, a 100 ns molecular dynamics simulation was conducted to assess the stability of the complex formed between the receptor 6VMZ and methyl α-d-mannopyranoside derivatives under in silico physiological conditions. The results revealed a stable conformation and binding pattern within the stimulating environment. In silico pharmacokinetic and toxicity assessments of the synthesized molecules were performed using Osiris software (version 2.9.1). Compounds 4 and 6 demonstrated favorable computational and pharmacological activities, albeit with a low drug score, possibly attributed to their higher molecular weight and irritancy. In conclusion, this study showcases the synthesis and evaluation of methyl α-d-mannopyranoside derivatives as promising candidates for antimicrobial and antifungal agents. Molecular docking and dynamics simulations, along with pharmacological predictions, contribute to our understanding of their potential therapeutic utility, although further research may be warranted to address certain pharmacological aspects.
Kayes M.R., Saha S., Alanazi M.M., Ozeki Y., Pal D., Hadda T.B., Legssyer A., M. A. Kawsar S.
Saudi Pharmaceutical Journal scimago Q2 wos Q2 Open Access
2023-11-01 citations by CoLab: 13 Abstract  
Macromolecules i.e., carbohydrate derivatives are crucial to biochemical and medical research. Herein, we designed and synthesized eight methyl α-D-glucopyranoside (MGP) derivatives (2-8) in good yields following the regioselective direct acylation method. The structural configurations of the synthesized MGP derivatives were analyzed and verified using multiple physicochemical and spectroscopic techniques. Antimicrobial experiments revealed that almost all derivatives demonstrated noticeable antifungal and antibacterial efficacy. The synthesized derivatives showed minimum inhibitory concentration (MIC) values ranging from 0.75 µg/mL to 1.50 µg/mL and minimum bactericidal concentrations (MBCs) ranging from 8.00 µg/mL to 16.00 µg/mL. Compound 6 inhibited Ehrlich ascites carcinoma (EAC) cell proliferation by 10.36% with an IC50 of 2602.23 μg/mL in the MTT colorimetric assay. The obtained results were further rationalized by docking analysis of the synthesized derivatives against 4URO and 4XE3 receptors to explore the binding affinities and nonbonding interactions of MGP derivatives with target proteins. Compound 6 demonstrated the potential to bind with the target with the highest binding energy. In a stimulating environment, a molecular dynamics study showed that MGP derivatives have a stable conformation and binding pattern. The MGP derivatives were examined using POM (Petra/Osiris/Molinspiration) bioinformatics, and as a result, these derivatives showed good toxicity, bioavailability, and pharmacokinetics. Various antifungal/antiviral pharmacophore (Oδ-, O’δ-) sites were identified by using POM investigations, and compound 6 was further tested against other pathogenic fungi and viruses, such as Micron and Delta mutants of SARS-CoV-2.
Lanka G., Begum D., Banerjee S., Adhikari N., P Y., Ghosh B.
2023-11-01 citations by CoLab: 43 Abstract  
Histone deacetylase 3 (HDAC3) is an epigenetic regulator that involves gene expression, apoptosis, and cell cycle progression, and the overexpression of HDAC3 is accountable for several cancers, neurodegeneracy, and many other diseases. Therefore, HDAC3 emerged as a promising drug target for the novel drug design. Here, we carried out the pharmacophore modeling using 50 benzamide-based HDAC3 selective inhibitors and utilized it for PHASE ligand screening to retrieve the hits with similar pharmacophore features. The dataset inhibitors of best hypotheses used to build the 3D QSAR model and the generated 3D QSAR model resulted in good PLS statistics with a regression coefficient (R2) of 0.89, predictive coefficient (Q2) of 0.88, and Pearson-R factor of 0.94 indicating its excellent predictive ability. The hits retrieved from pharmacophore-based virtual screening were subjected to docking against HDAC3 for the identification of potential inhibitors. A total of 10 hitsM1 to M10 were ranked using their scoring functions and further subject to lead optimization. The Prime MM/GBSA, AutoDock binding free energies, and ADMET studies were implemented for the selection of lead candidates. The four ligand molecules M1, M2, M3, and M4 were identified as potential leads against HDAC3 after lead optimization. The top two leads M1 and M2 were subjected to MD simulations for their stability evaluation with HDAC3. The newly designed leads M11 and M12 were identified as HDAC3 potential inhibitors from MD simulations studies. Therefore, the outcomes of the present study could provide insights into the discovery of new potential HDAC3 inhibitors with improved selectivity and activity against a variety of cancers and neurodegenerative diseases.
Shahwan M., Hassan N., Ashames A., Alrouji M., Alhumaydhi F., Al Abdulmonem W., Muhsinah A.B., Furkan M., Khan R.H., Shamsi A., Akhtar A.
2023-08-01 citations by CoLab: 17 Abstract  
Sphingosine kinase 1 (SphK1) has been widely recognized as a significant contributor to various types of cancer, including breast, lung, prostate, and hematological cancers. This research aimed to find a potential SphK1 inhibitor through a step-by-step virtual screening of PF543 (a known SphK1 inhibitor)-like compounds obtained from the PubChem library with the Tanimoto threshold of 80 %. The virtual screening process included several steps, namely physicochemical and ADMET evaluation, PAINS filtering, and molecular docking, followed by molecular dynamics (MD) simulation and principal component analysis (PCA). The results showed that compound CID:58293960 ((3R)-1,1-dioxo-2-[[3-[(4-phenylphenoxy)methyl]phenyl]methyl]-1,2-thiazolidine-3-carboxylic acid) demonstrated high potential as SphK1 inhibitor. All-atom MD simulations were performed for 100 ns to evaluate the stability and structural changes of the docked complexes in an aqueous environment. The analysis of the time evolution data of structural deviations, compactness, PCA, and free energy landscape (FEL) indicated that the binding of CID:58293960 with SphK1 is relatively stable throughout the simulation. The results of this study provide a platform for the discovery and development of new anticancer therapeutics targeting SphK1.
Alamri M.A., Alawam A.S., Alshahrani M.M., Kawsar S.M., Prinsa, Saha S.
Molecules scimago Q1 wos Q2 Open Access
2023-06-28 citations by CoLab: 10 PDF Abstract  
The RAS gene family is one of the most frequently mutated oncogenes in human cancers. In KRAS, mutations of G12D and G12C are common. Here, 52 iridoids were selected and docked against 8AFB (KRAS G12C receptor) using Sotorasib as the standard. As per the docking interaction data, 6-O-trans-p-coumaroyl-8-O-acetylshanzhiside methyl ester (dock score: −9.9 kcal/mol), 6′-O-trans-para-coumaroyl geniposidic acid (dock score: −9.6 kcal/mol), 6-O-trans-cinnamoyl-secologanoside (dock score: −9.5 kcal/mol), Loganic acid 6′-O-beta-d-glucoside (dock score: −9.5 kcal/mol), 10-O-succinoylgeniposide (dock score: −9.4), Loganic acid (dock score: −9.4 kcal/mol), and Amphicoside (dock score: −9.2 kcal/mol) showed higher dock scores than standard Sotorasib (dock score: −9.1 kcal/mol). These common amino acid residues between iridoids and complexed ligands confirmed that all the iridoids perfectly docked within the receptor’s active site. The 100 ns MD simulation data showed that RMSD, RMSF, radius of gyration, and SASA values were within range, with greater numbers of hydrogen bond donors and acceptors. MM/PBSA analysis showed maximum binding energy values of −7309 kJ/mol for 6-O-trans-p-coumaroyl-8-O-acetylshanzhiside methyl ester. FMO analysis showed that 6-O-trans-p-coumaroyl-8-O-acetylshanzhiside methyl ester was the most likely chemically reactive molecule. MEP analysis data highlighted the possible electrophilic and nucleophilic attack regions of the best-docked iridoids. Of all the best-docked iridoids, Loganic acid passed Lipinski, Pfizer, and GSK filters with a similar toxicity profile to Sotorasib. Thus, if we consider these iridoids to be KRAS G12C inhibitors, they will be a boon to mankind.

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