Diseño y evaluación in silico de nuevos derivados del pirrol BM212 como inhibidores de la proteína MmpL3.

Abstract

One of the biggest challenges in the search for new bioactive compounds against Mycobacterium tuberculosis (Mtb) is the presence of a strong hydrophobic barrier that prevents the penetration of drugs through the cell wall, causing the appearance of drug resistance. Drug-resistant strains continue to drive scientific research in the search for mechanisms to control this disease, evidencing a clear need to discover new drugs and drug targets to treat these difficult-to-control bacterial infections. (Bolla, J., 2020; Rayasam, G., 2014). On the other hand, considering that the MmpL3 protein is responsible for the biogenesis of the mycobacterial cell wall and the transport of trehalose monomycolate (TMM) which is a structural unit of this cell wall. Given this function, MmpL3 is considered as a potential therapeutic target and has been the focus of many ongoing research efforts, since its inhibition blocks the passage of TMM through the inner membrane, weakening the cell wall of mycobacteria causing the cell death. (Bhakhar et al., 2021; Shao et al., 2020; Munnaluri et al., 2019). In the search for MmpL3 inhibitors, different structures with promising activity against this molecular target have been found. Among these compounds, pyrrole BM212 stands out; a potent inhibitor against multiresistant Mtb strains and one of the most promising compounds against this molecular target, which constitutes a suitable base structure for an optimization process. (Poce et al., 2019; Gaikwad et al., 2021; Wavhale et al., 2017). The purpose of our research work was to identify the substitution pattern crucial to enhance the antimycobacterial activity of the lead molecule BM212. To this end, using an in-silico approach, the BM212 scaffold was systematically explored by making modifications at the N1, C3 and C5 positions of pyrrole, followed by ADME property assessments, molecular/dynamic learning in order to understand the structure relationships. -activity (SAR) of said molecule. In this way, the key parameters to improve the potential activity of the ligands were identified; According to the evaluations of concentration and molecular dynamics, a new series of compounds with better affinity for the MmpL3 binding site will be improved and, in turn, possible candidates for drugs as a synergistic treatment to the current therapeutic procedures for tuberculosis.