Exploring the Multifaceted Pharmacological Potential of Griseofulvin: From Genomic Insights to Therapeutic Applications

Abstract

Griseofulvin (C17H17ClO6) is a natural compound first isolated from Penicillium griseofulvum in 1939. Besides Penicillium, it can also be found in other types of fungi such as Xylaria flabelliformis, Abieticola koreana, and Stachybotrys levispora. Its applications span agriculture and medicine: in agriculture, griseofulvin acts as a protective agent against fungal infections in crops, while in medicine, it serves as a low-toxicity antifungal treatment for ringworm and dermatophyte infections in both humans and animals. In cancer research, griseofulvin has shown potential by inhibiting cancer cell division, possibly inducing cell death through its interaction with microtubules in the mitotic spindle. Furthermore, griseofulvin exhibits promising activity against hepatitis C virus by disrupting microtubule formation in human cells, thereby inhibiting viral replication. These diverse applications underscore the broad utility of griseofulvin across different fields, suggesting further avenues for exploration in therapeutic and biotechnological contexts. This research encompasses four distinct chapters, each probing different aspects of griseofulvin and its derivatives. The first chapter introduces griseofulvin, presenting an extensive review of both past and current knowledge on the subject. It provides a foundation for understanding the compound's properties and uses, setting the stage for the subsequent chapters. The second chapter explores the genomic evidence pertaining to the preservation and distribution of genes involved in griseofulvin biosynthesis across various fungal species. Through comprehensive sequencing and comparative genomic analyses, the study sheds light on the evolutionary dynamics and ecological significance of the gsf gene cluster, which orchestrates the synthesis of griseofulvin, a bioactive compound with antifungal properties. By examining multiple fungal genomes, the research elucidates patterns of gene conservation and divergence, providing insights into the evolutionary forces shaping the distribution of griseofulvin-producing fungi. Furthermore, the identification of conserved gsf genes and their shared sequence orders among fungal species offers valuable insights into the functional roles and evolutionary constraints governing griseofulvin biosynthesis. We hypothesize that nonessential gsf genes would provide minimal evolutionary benefit, leading to these genes accumulating significant sequence variability or being completely lost in the gsf BGC of many fungal genomes. Overall, this study contributes to our understanding of the genetic basis of griseofulvin production in fungi and lays the groundwork for future research aimed at harnessing the therapeutic potential of this bioactive compound. Subsequently, the third chapter investigates the therapeutic potential of griseofulvin and its derivatives against COVID-19 through computational molecular dynamics simulations. With the urgent need for effective treatments against the novel coronavirus, this study explores the binding interactions between griseofulvin compounds and key viral proteins implicated in the replication and transcription processes of SARS-CoV-2. Through in silico analyses, the research identifies promising candidates among griseofulvin derivatives that exhibit significant binding affinity to essential viral proteins, such as the main protease (6LU7), ACE2 receptor, receptor-binding domain (RBD), and RNA-dependent RNA polymerase (RdRp). We hypothesize that griseofulvin and its derivatives can effectively inhibit SARS-CoV-2 by binding to the virus's main protease, RdRp, and RDB proteins, as well as the human ACE2 receptor. Molecular docking and molecular dynamics simulations will reveal strong interactions between these compounds and the target proteins. These findings highlight the potential of griseofulvin derivatives as inhibitors of COVID-19 viral replication and offer valuable insights for further experimental validation and drug development efforts aimed at combating the ongoing global pandemic. The fourth chapter undertakes a thorough investigation into the antibacterial properties of newly formulated derivatives of griseofulvin using computational techniques. Utilizing molecular docking and molecular dynamics simulations, the study assesses how these derivatives interact and remain stable when bound to bacterial targets such as penicillin-binding protein 2 (PBP2), tyrosine phosphatase, and filamenting temperature-sensitive mutant Z (FtsZ) protein. The research identifies critical structural characteristics necessary for antibacterial effectiveness, including the presence of a β-lactam moiety, sulfonyl group, and chlorine substitution. Notably, certain derivatives exhibit robust binding affinities and stability within the active sites of bacterial proteins, suggesting their potential as potent antibacterial agents. The hypothesis posits that deliberate structural adjustments to griseofulvin can enhance its antibacterial properties, positioning it as a promising candidate for new antibiotic development. These findings offer significant insights for the strategic design and advancement of griseofulvin derivatives with enhanced antibacterial activity, presenting promising avenues for combatting bacterial infections and addressing the challenge of antibiotic resistance.