Developing a new drug against trichomoniasis, new inhibitory compounds of the protein triosephosphate isomerase

Potential Site to Direct Selective Compounds in the Triosephosphate Isomerase for the Development of New Drugs

“…In the pharmaceutical industry, the development of selective drugs to an enzyme or the repositioning of commercial drugs, today, is booming. The glycolytic enzyme triosephosphate isomerase (TIM) has been used as a therapeutic target for the development of new drugs against various pathogenic organisms, such as, Trypanosoma cruzi, Trypanosoma brucei, Entamoeba histolytica, Giardia duodenalis, Trichomonas vaginalis , among others . Therefore, saving resources in the development of new drugs, by directing the interaction of pharmacological compounds to a specific interaction site with a high probability to be selective, represents an opportunity, for researchers who are looking for new molecules or pharmacological compounds that they do not have a reported use, or in the case, of wanting to find another use to conventional drugs, such as omeprazole against TIM [11] [12] .…”

“…Proposing a specific sequence for this enzyme (TIM), with an effect on glycolytic activity and that has no effect on HsTIM, is a challenge, so, in this study, recombinant TIMs from different organisms were used to determine a consensus sequence key to get an interaction with the majority 34 compounds used, these compounds were selected by a Docking (almost 450,000 compounds of Chembridge corp.), using the crystallographic structure of the TIM of Trichomonas vaginalis (3QST), this enzyme has been extensively studied [26] [27] and it serves as a base structure to choose compounds against TIMs. Theses 34 compounds (Supplementary Table S1) were tested in in vitro assays of enzymatic activity with recombinant TIMs from different organisms ( Trichomonas vaginalis, Burkholderia thailandensis, Clostridium perfringens, Nostoc punctiforme, Thermus thermophiles, Streptomyces coelicolor, Deinococcus radiodurans, and Homo sapiens) .…”

“…34 Compounds that were selected by Docking directed to potential sites that are poorly conserved in the HsTIM were used (Supplementary Table S1), which these have a high probability of having interaction in TIMs of other organisms, and that are a possible new drug to develop.…”

“…It is determined that compound 3 and 7 , have a decrease in enzymatic activity of 70 and 40% respectively (Figure A) …”

“…It is noticeable that residues F46, Y103 and K224, are not conserve in HsTIM sequence and could be important in the selectivity of compound against TIMs (Figure ). The interaction of the some conformers is between the loop 3, the interface and the loop 6, as already reported, the interaction of compounds in loop 3, 6 and 7 have an effect on enzymatic activity, here it is confirmed on others TIMs. These eight compounds, each one alters one of these loop, we propose that mainly loop 6, in this way it is introduced into the active site, which the region of residues Y209, G210, G211, S212, V213 and K214 favors interaction between compound and the space, and thus the interaction can develop.…”