Identification of potential mycobacterium tuberculosis beta-ketoacyl synthase inhibitors by virtual screening

Abstract

Tuberculosis (TB) is a serious public health problem because of its continued dissemination. The necessity of new and effective drugs is evident for better TB control and, to achieve this goal the key enzyme beta-ketoacyl synthase (EC 2.3.1.41) has been selected, due to its action on the synthesis of mycolic acids, and essential step to the survival of the microorganism. So, this study aimed to identify new molecular entities capable of interacting with beta-ketoacyl synthase, using virtual screening approaches. For virtual screening DOCK 6.5 program and ZINC data bank fragments has been used. After ranking the compounds by number, the top 100 structures were analyzed with the SOM algorithm available in AuPosSOM server. Intermolecular interactions resulting from the groupings generated by AuPosSOM were analyzed, and with that, new chemical entities were proposed. The theoretical affinity of these new compounds was tested against the enzyme under study. The results showed that the fragment ZINC51860757 got better affinity for the enzyme and the theoretical molecule LMM7, obtained from structural modification of the original fragment, obtained energy gain and kept the standard intermolecular interactions. Based on the strategy centred on the target structure, virtual screening enable to test the putative activity before the compound is subjected to in vitro assays, allowing a greater planning and targeting, it can greatly reduce the cost and time employed in new drug research.