Computational analysis of [Au(L)X] complexes as targeted Leishmania metallodrugs

Abstract

Leishmania protozoan parasites cause leishmaniasis, a disease with a range of clinical manifestations in humans, transmitted by sandfly bites. According to the World Health Organization, it is endemic in 88 countries and affects 12 million people worldwide, classified as one of the most neglected tropical diseases. Leishmaniasis control is puzzling, particularly in Brazil, where it has been spreading across the country, leading to an increase in the number of cases in urbanized areas. Drug options to treat patients are limited, with antimonials having remained as the first line of treatment for all forms of leishmaniasis for almost a century, even though they are toxic and require painful parenteral administration. Cysteine proteases (CP), trypanothione reductase (TR) and zinc finger (ZF) domains are essential proteins/enzymes for parasite survival and replication, thus, they are significant molecular targets for drug design. So, in medicinal inorganic chemistry, it is of great interest to investigate the interaction of metallodrugs with specific targets. In silico (i.e., computational) methods are widely used in the research and development of drugs. However, the implementation of computational methods to study metallodrugs are limited. In silico studies of coordination complexes, including metallodrugs, require more computational resources and a more sophisticated interpretation. Additionally, in a biological medium, coordination complexes are more likely to undergo parallel reactions such as ligand substitutions and redox processes compared to most conventional organic compounds. Currently, computational studies of the interactions of metallopharmaceuticals and protein targets are mostly limited to the application of DFT calculations on simplified systems, for example, single amino acids or some relevant residues in the active site. Previous works, including ours1,2, Tolbatov's3 and Goetzfried's4, have explored simulations in this direction. Another approach is the use of docking that disregards ligand exchange or electron transfer reactions5. A few examples include hybrid calculations which have the potential to viably increase the scale and accuracy of these biological simulations. For instance, Laskay et al.6 employed QM/MM calculations to support transmetallation experimental results of zinc finger proteins by other metals. De Almeida et al7 conducted DFT and MD simulations to interpret the inhibition of aquaporin-3 (AQP-3) by a gold(III) complex. The DFT supplied the correlation between cysteine affinity and ligand structure and parameters to perform MD in the AQP-3 after gold binding. Finally, the computational results showed how protein is affected by gold binding in agreement with the inhibition assays. Gold(I) complexes, investigated as potential chemotypes for leishmania metallodrugs, commonly exhibit a linear geometry and a coordination number of two. These complexes are often represented by the general formula [Au(L)X], where L represents a strong binding carrier ligand (namely N-heterocyclic carbene, NHC, and phosphine ligands), and X denotes a labile leaving group. The structure of these ligands significantly influences the physicochemical properties of the resulting complexes, leading to variations in their in vitro and in vivo activities. One of the main challenges of medicinal inorganic chemistry is to create targeted therapies. Our research group has studied the design of ligands to promote targeting metallodrugs, especially those of Au(I), Cu(I), Pt(II) and Pd(II)8,9,10. Among different approaches, we propose to bioconjugate peptides or nucleotides to the metallocompounds as a strategy for targeting.In this context, this study aims to apply in silico methods to investigate the influence of the coordination sphere of [Au(L)X] complexes, on their binding to molecular targets of interest, such as CP, TR, and ZF proteins. (AU)