A consensus reverse docking approach for identification of a competitive inhibitor of acetyltransferase enhanced intracellular survival protein from Mycobacterium tuberculosis.

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb), which remains a significant global health challenge. The emergence of multidrug-resistant (MDR) Mtb strains imposes the development of new therapeutic strategies. This study focuses on the identification and evaluation of potential inhibitors against Mtb H37Ra through a comprehensive screening of an in-house chemolibrary. Subsequently, a promising pyrimidine derivative (LQM495) was identified as promising and then further investigated by experimental and in silico approaches. In this context, computational techniques were used to elucidate the potential molecular target underlying the inhibitory action of LQM495. Then, a consensus reverse docking (CRD) protocol was used to investigate the interactions between this compound and several Mtb targets. Out of 98 Mtb targets investigated, the enhanced intracellular survival (Eis) protein emerged as a target for LQM495. To gain insights into the stability of the LQM495-Eis complex, molecular dynamics (MD) simulations were conducted over a 400 ns trajectory. Further insights into its binding modes within the Eis binding site were obtained through a Quantum mechanics (QM) approach, using density functional theory (DFT), with B3LYP/D3 basis set. These calculations shed light on the electronic properties and reactivity of LQM495. Subsequently, inhibition assays and kinetic studies of the Eis activity were used to investigate the activity of LQM495. Then, an IC50 value of 11.0 ± 1.4 µM was found for LQM495 upon Eis protein. Additionally, its Vmax, Km, and Ki parameters indicated that it is a competitive inhibitor. Lastly, this study presents LQM495 as a promising inhibitor of Mtb Eis protein, which could be further explored for developing novel anti-TB drugs in the future.

Insights on Dengue and Zika NS5 RNA-dependent RNA polymerase (RdRp) inhibitors.

Over recent years, many outbreaks caused by (re)emerging RNA viruses have been reported worldwide, including life-threatening Flaviviruses, such as Dengue (DENV) and Zika (ZIKV). Currently, there is only one licensed vaccine against Dengue, Dengvaxia®. However, its administration is not recommended for children under nine years. Still, there are no specific inhibitors available to treat these infectious diseases. Among the flaviviral proteins, NS5 RNA-dependent RNA polymerase (RdRp) is a metalloenzyme essential for viral replication, suggesting that it is a promising macromolecular target since it has no human homolog. Nowadays, several NS5 RdRp inhibitors have been reported, while none inhibitors are currently in clinical development. In this context, this review constitutes a comprehensive work focused on RdRp inhibitors from natural, synthetic, and even repurposing sources. Furthermore, their main aspects associated with the structure-activity relationship (SAR), proposed mechanisms of action, computational studies, and other topics will be discussed in detail.