Drug to genome to drug: a computational large-scale chemogenomics screening for novel drug candidates against sporotrichosis.

Sporotrichosis is recognized as the predominant subcutaneous mycosis in South America, attributed to pathogenic species within the Sporothrix genus. Notably, in Brazil, Sporothrix brasiliensis emerges as the principal species, exhibiting significant sapronotic, zoonotic and enzootic epidemic potential. Consequently, the discovery of novel therapeutic agents for the treatment of sporotrichosis is imperative. The present study is dedicated to the repositioning of pharmaceuticals for sporotrichosis therapy. To achieve this goal, we designed a pipeline with the following steps: (a) compilation and preparation of Sporothrix genome data; (b) identification of orthologous proteins among the species; (c) identification of homologous proteins in publicly available drug-target databases; (d) selection of Sporothrix essential targets using validated genes from Saccharomyces cerevisiae; (e) molecular modeling studies; and (f) experimental validation of selected candidates. Based on this approach, we were able to prioritize eight drugs for in vitro experimental validation. Among the evaluated compounds, everolimus and bifonazole demonstrated minimum inhibitory concentration (MIC) values of 0.5 µg/mL and 4.0 µg/mL, respectively. Subsequently, molecular docking studies suggest that bifonazole and everolimus may target specific proteins within S. brasiliensis- namely, sterol 14-α-demethylase and serine/threonine-protein kinase TOR, respectively. These findings shed light on the potential binding affinities and binding modes of bifonazole and everolimus with their probable targets, providing a preliminary understanding of the antifungal mechanism of action of these compounds. In conclusion, our research advances the understanding of the therapeutic potential of bifonazole and everolimus, supporting their further investigation as antifungal agents for sporotrichosis in prospective hit-to-lead and preclinical investigations.

Repurposing miconazole and tamoxifen for the treatment of Mycobacterium abscessus complex infections through in silico chemogenomics approach.

Drug repositioning is an alternative to overcome the complexity of the drug discovery and approval procedures for the treatment of Mycobacterium abscessus Complex (MABSC) infections that are increasing globally due to the emergency of antimicrobial resistance mechanisms. Here, an in silico chemogenomics approach was performed to compare the sequences from 4942 M. abscessus subsp. abscessus (M. abscessus) proteins with 5258 or 3473 therapeutic targets registered in the DrugBank or Therapeutic Target Database, respectively. This comparison identified 446 drugs or drug candidates whose targets were homologous to M. abscessus proteins. These identified drugs were considered potential inhibitors of MABSC (anti-MABSC activity). Further screening and inspection resulted in the selection of ezetimibe, furosemide, itraconazole, miconazole (MCZ), tamoxifen (TAM), and thiabendazole (THI) for experimental validation. Among them, MCZ and TAM showed minimum inhibitory concentrations (MIC) of 32 and 24 µg mL-1 against M. abscessus, respectively. For M. bolletii and M. massiliense strains, MCZ and TAM showed MICs of 16 and 24 µg mL-1, in this order. Subsequently, the antibacterial activity of MCZ was confirmed in vivo, indicating its potential to reduce the bacterial load in the lungs of infected mice. These results show that MCZ and TAM can serve as molecular scaffolds for the prospective hit-2-lead optimization of new analogs with greater potency, selectivity, and permeability.

In silico-chemogenomic repurposing of new chemical scaffolds for histoplasmosis treatment.

BACKGROUND: Histoplasmosis is a systemic form of endemic mycosis to the American continent and may be lethal to people living with HIV/AIDS. The drugs available for treating histoplasmosis are limited, costly, and highly toxic. New drug development is time-consuming and costly; hence, drug repositioning is an advantageous strategy for discovering new therapeutic options. OBJECTIVE: This study was conducted to identify drugs that can be repositioned for treating histoplasmosis in immunocompromised patients. METHODS: Homologous proteins among Histoplasma capsulatum strains were selected and used to search for homologous targets in the DrugBank and Therapeutic Target Database. Essential genes were selected using Saccharomyces cerevisiae as a model, and functional regions of the therapeutic targets were analyzed. The antifungal activity of the selected drugs was verified, and homology modeling and molecular docking were performed to verify the interactions between the drugs with low inhibitory concentration values and their corresponding targets. RESULTS: We selected 149 approved drugs with potential activity against histoplasmosis, among which eight were selected for evaluating their in vitro activity. For drugs with low minimum inhibitory concentration values, such as mebendazole, everolimus, butenafine, and bifonazole, molecular docking studies were performed. A chemogenomic framework revealed lanosterol 14-α-demethylase, squalene monooxygenase, serine/threonine-protein kinase mTOR, and the ß-4B tubulin chain of H. capsulatum, respectively, as the protein targets of the drugs. CONCLUSIONS: Our strategy can be used to identify promising antifungal targets, and drugs with repositioning potential for treating H. capsulatum.