Computational Design of Novel Griseofulvin Derivatives Demonstrating Potential Antibacterial Activity: Insights from Molecular Docking and Molecular Dynamics Simulation.

In response to the urgent demand for innovative antibiotics, theoretical investigations have been employed to design novel analogs. Because griseofulvin is a potential antibacterial agent, we have designed novel derivatives of griseofulvin to enhance its antibacterial efficacy and to evaluate their interactions with bacterial targets using in silico analysis. The results of this study reveal that the newly designed derivatives displayed the most robust binding affinities towards PBP2, tyrosine phosphatase, and FtsZ proteins. Additionally, molecular dynamics (MD) simulations underscored the notable stability of these derivatives when engaged with the FtsZ protein, as evidenced by root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), and solvent-accessible surface area (SASA). Importantly, this observation aligns with expectations, considering that griseofulvin primarily targets microtubules in eukaryotic cells, and FtsZ functions as the prokaryotic counterpart to microtubules. These findings collectively suggest the promising potential of griseofulvin and its designed derivatives as effective antibacterial agents, particularly concerning their interaction with the FtsZ protein. This research contributes to the ongoing exploration of novel antibiotics and may serve as a foundation for future drug development efforts.

In Silico Exploration of Microtubule Agent Griseofulvin and Its Derivatives Interactions with Different Human ß-Tubulin Isotypes.

Tubulin isotypes are known to regulate microtubule stability and dynamics, as well as to play a role in the development of resistance to microtubule-targeted cancer drugs. Griseofulvin is known to disrupt cell microtubule dynamics and cause cell death in cancer cells through binding to tubulin protein at the taxol site. However, the detailed binding mode involved molecular interactions, and binding affinities with different human ß-tubulin isotypes are not well understood. Here, the binding affinities of human ß-tubulin isotypes with griseofulvin and its derivatives were investigated using molecular docking, molecular dynamics simulation, and binding energy calculations. Multiple sequence analysis shows that the amino acid sequences are different in the griseofulvin binding pocket of ßI isotypes. However, no differences were observed at the griseofulvin binding pocket of other ß-tubulin isotypes. Our molecular docking results show the favorable interaction and significant affinity of griseofulvin and its derivatives toward human ß-tubulin isotypes. Further, molecular dynamics simulation results show the structural stability of most ß-tubulin isotypes upon binding to the G1 derivative. Taxol is an effective drug in breast cancer, but resistance to it is known. Modern anticancer treatments use a combination of multiple drugs to alleviate the problem of cancer cells resistance to chemotherapy. Our study provides a significant understanding of the involved molecular interactions of griseofulvin and its derivatives with ß-tubulin isotypes, which may help to design potent griseofulvin analogues for specific tubulin isotypes in multidrug-resistance cancer cells in future.

Structural evolution of Delta lineage of SARS-CoV-2.

One of the main obstacles in prevention and treatment of COVID-19 is the rapid evolution of the SARS-CoV-2 Spike protein. Given that Spike is the main target of common treatments of COVID-19, mutations occurring at this virulent factor can affect the effectiveness of treatments. The B.1.617.2 lineage of SARS-CoV-2, being characterized by many Spike mutations inside and outside of its receptor-binding domain (RBD), shows high infectivity and relative resistance to existing cures. Here, utilizing a wide range of computational biology approaches, such as immunoinformatics, molecular dynamics (MD), analysis of intrinsically disordered regions (IDRs), protein-protein interaction analyses, residue scanning, and free energy calculations, we examine the structural and biological attributes of the B.1.617.2 Spike protein. Furthermore, the antibody design protocol of Rosetta was implemented for evaluation the stability and affinity improvement of the Bamlanivimab (LY-CoV55) antibody, which is not capable of interactions with the B.1.617.2 Spike. We observed that the detected mutations in the Spike of the B1.617.2 variant of concern can cause extensive structural changes compatible with the described variation in immunogenicity, secondary and tertiary structure, oligomerization potency, Furin cleavability, and drug targetability. Compared to the Spike of Wuhan lineage, the B.1.617.2 Spike is more stable and binds to the Angiotensin-converting enzyme 2 (ACE2) with higher affinity.

Griseofulvin: An Updated Overview of Old and Current Knowledge.

Griseofulvin is an antifungal polyketide metabolite produced mainly by ascomycetes. Since it was commercially introduced in 1959, griseofulvin has been used in treating dermatophyte infections. This fungistatic has gained increasing interest for multifunctional applications in the last decades due to its potential to disrupt mitosis and cell division in human cancer cells and arrest hepatitis C virus replication. In addition to these inhibitory effects, we and others found griseofulvin may enhance ACE2 function, contribute to vascular vasodilation, and improve capillary blood flow. Furthermore, molecular docking analysis revealed that griseofulvin and its derivatives have good binding potential with SARS-CoV-2 main protease, RNA-dependent RNA polymerase (RdRp), and spike protein receptor-binding domain (RBD), suggesting its inhibitory effects on SARS-CoV-2 entry and viral replication. These findings imply the repurposing potentials of the FDA-approved drug griseofulvin in designing and developing novel therapeutic interventions. In this review, we have summarized the available information from its discovery to recent progress in this growing field. Additionally, explored is the possible mechanism leading to rare hepatitis induced by griseofulvin. We found that griseofulvin and its metabolites, including 6-desmethylgriseofulvin (6-DMG) and 4- desmethylgriseofulvin (4-DMG), have favorable interactions with cytokeratin intermediate filament proteins (K8 and K18), ranging from -3.34 to -5.61 kcal mol-1. Therefore, they could be responsible for liver injury and Mallory body (MB) formation in hepatocytes of human, mouse, and rat treated with griseofulvin. Moreover, the stronger binding of griseofulvin to K18 in rodents than in human may explain the observed difference in the severity of hepatitis between rodents and human.

In Silico Molecular Dynamics of Griseofulvin and Its Derivatives Revealed Potential Therapeutic Applications for COVID-19.

Treatment options for Coronavirus Disease 2019 (COVID-19) remain limited, and the option of repurposing approved drugs with promising medicinal properties is of increasing interest in therapeutic approaches to COVID-19. Using computational approaches, we examined griseofulvin and its derivatives against four key anti-SARS-CoV-2 targets: main protease, RdRp, spike protein receptor-binding domain (RBD), and human host angiotensin-converting enzyme 2 (ACE2). Molecular docking analysis revealed that griseofulvin (CID 441140) has the highest docking score (-6.8 kcal/mol) with main protease of SARS-CoV-2. Moreover, griseofulvin derivative M9 (CID 144564153) proved the most potent inhibitor with -9.49 kcal/mol, followed by A3 (CID 46844082) with -8.44 kcal/mol against M protease and ACE2, respectively. Additionally, H bond analysis revealed that compound A3 formed the highest number of hydrogen bonds, indicating the strongest inhibitory efficacy against ACE2. Further, molecular dynamics (MD) simulation analysis revealed that griseofulvin and these derivatives are structurally stable. These findings suggest that griseofulvin and its derivatives may be considered when designing future therapeutic options for SARS-CoV-2 infection.

Anticancer activity and evaluation of apoptotic genes expression of 2-azetidinones containing anthraquinone moiety.

Nowadays, one of the principal causes of death in the world is cancer. A series of 2-azetidinones containing anthraquinone moiety with various substituents were synthesized using [2 + 2] ketene-imine cycloaddition (Staudinger ketene-imine cycloaddition), and their cytotoxicity against some human cancer and normal cell lines was evaluated. Some of these hybrid compounds showed moderate to significant cytotoxicity against breast carcinoma (MCF7), colon carcinoma (HCT116), prostate carcinoma (PC3), and neuroblastoma (SKNMC) cell lines via MTT assay. Surprisingly, hybrid 4gh with the best anticancer activity demonstrated very good antibacterial and antifungal activities. This compound was selected to study to test on human fibroblast (Hu02) normal cell and comparison with doxorubicin. While 2-azetidinone 4gh represented similar cytotoxicity against cancer cell lines compared to doxorubicin, the 2-azetidinone demonstrated lower cytotoxicity against human fibroblast (Hu02) than doxorubicin. Further real-time PCR investigation displayed the expression of Bcl-xl, KI-67, TPX2 and BAX genes were significantly increased or decreased as desired in the cancer cell lines studied by treatment with doxorubicin or 2-azetidinone-anthraquinone 4gh. Molecular docking studies represented that hybrid 4gh strongly fitted the active site of topoisomerase II (PDB 4G0V) with hydrogen bond and hydrophobic interactions.

Synthesis, in vitro biological evaluation and in silico molecular docking studies of novel ß-lactam-anthraquinone hybrids.

Schiff bases from 2-aminoanthraquinone have been prepared by reaction with aldehydes and used to prepare novel ß-lactam-anthraquinone hybrids via [2+2] ketene-imine cycloaddition (Staudinger reaction) reaction. In vitro antibacterial studies of all synthesized compound were carried out against three gram-positive strains Staphylococcus aureus (Methicillin-resistant strain), Enterococcus faecium (Vancomycin-resistant strain) and Bacillus subtilis, and two gram-negative strains Escherichia coli and Pseudomonas aeruginosa. These compounds were further evaluated for their in vitro antifungal activity against Candida albicans, Aspergillus niger and Trichophyton mentagrophytes. Hybrid compounds showed moderate to excellent antibacterial and antifungal activities. Surprisingly, among the tested compounds, some of them revealed equal antibacterial and antifungal properties and even better than standards. In addition, results demonstrated that the new hybrids are very promising antibacterial agents against resistant strains. Also molecular docking studies were carried out by Autodoc software. Penicillin-binding protein 2a (PDB ID: 1VQQ) from methicillin-resistant Staphylococcus aureus strain used as a target which good binding interactions were observed.