Chemoinformatics: Directions Toward Combating Neglected Diseases

Protozoan infections are parasitic diseases that affect hundreds and millions of people worldwide, but have been largely neglected for drug development because they affect poor people in poor regions of the world. Most of the current drugs used to treat these diseases are decades old and have many limitations, including the emergence of drug resistance. This review will focus on the most recent developments, from 2001 to 2008, published in the field of patents and publications, paying particular attention to promising compounds acting against trypanosomiasis, leishmaniasis, malaria, toxoplasmosis, amebiasis, giardiasis, balantidiasis and pneumocystosis, their chemistry and biological evaluation, and to new chemical and pharmaceutical processes.

Several techniques have been used to study the mechanisms by which receptors recognize ligands, one of them being quantitative structure activity relationship analysis of compounds. This method facilitates the description of molecular details involved in drug recognition by molecular receptors, as well as the molecular mechanism involved. This technique constitutes an essential tool to investigate chemical, electronic, and structural features affecting the leishmanicidal activity of compounds. However, few studies address this topic in Leishmania. Efforts should be made to stimulate research in this area and thus describe the characteristics of leishmanicidal drugs and their interaction with molecular receptors. The present chapter summarizes progress made recently in quantitative structure activity relationship studies of leishmanicidal compounds in experimental and in vivo scenarios. The review highlights possible critical spots in drug design and discusses the potential activity of compounds against different strains of the parasite as a way to optimize the treatment of leishmaniasis.

Homology modeling may be a very useful tool to obtain theoretical 3D structures of molecular targets when their experimental structures are still unknown. If 3D structures of the appropriate templates are available, it is possible to build a very consistent model using one of several softwares available today for this purpose and, further, use it to analyze the overall target structure, its active site residues and possible interactions with potential ligands. These models can also be used for further MD simulations, docking and QSAR studies in order to afford additional information toward the rational design of inhibitors to the molecular target in focus. Literature has reported some interesting studies using this approach on neglected diseases, especially malaria. Those studies have afforded very useful models for the design of more selective and powerful antimalarial agents.

Since its discovery in 1964 by Hansch, the Quantitative Structure Activity Relationship (QSAR) has remained an important tool in drug design. The work of a huge number of scientists has improved the strength, utility and efficiency of this vital technique in molecular modeling. The original formulation of the method was in two dimensions, the molecular descriptors i.e., the physico-chemical constants were correlated with the biological activity, however, advances in technology, computational efficiency and the brilliant ideas of researchers have added many descriptors/dimensions leading to the 3D, 4D, 5D and 6DQSAR techniques. The different forms of QSAR have not only contributed to understanding the pharmacophoric features required for improvement in the activity but has also helped to improve the pharmacokinetic and pharmacodynamic characteristics of drug candidates. The beauty of the QSAR technique is that it does not require information about the receptor (though well and good if known) and hence is helpful in the design and improvement of probable drug molecules not only against vital diseases/disorders but even against those which were long neglected. The diseases of tropical countries have been neglected for two reasons, poverty in these regions and remoteness to the developed parts of the world. The diseases which are top on this list are malaria, tuberculosis, leshmaniasis etc. However, in recent times the scenario has changed with many organizations, governments and research institutions showing an interest in eradicating such diseases mainly due to the serious problems of drug resistance. Under these circumstances, QSAR provides a good weapon for the design of novel candidates. Many QSAR studies have been reported in the literature both on the molecules synthesized and tested against the whole micro organism and also on molecules directed against specific targets of the micro organisms. This chapter will briefly cover the basics of the QSAR technique and will be followed by examples of the discovery of antitubercular agents through the QSAR methodology.

Molecular dynamics simulations have showed to be powerful tools when applied to the preliminary investigations of the interactions of potential molecular targets with its natural subtracts or, eventually, with their potential inhibitors. When the 3D structure of a molecular target is yet unknown, sometimes it is possible to build a very consistent model using one of the several softwares available today for this purpose (see chapter on homology modeling) and, further, use it to analyze the overall structure of the target, the active site residues and their potential interactions with potential ligands, by performing MD simulations studies in order to afford additional information towards the rational design of inhibitors to the molecular target in focus. Literature has reported a few interesting studies using this approach on leishmaniasis. Those studies have afforded useful information for the experimentalists on new drug targets for the rational design of new, more selective and powerful antileishmiasis agents.

Chagas disease (American trypanosomiasis) is one of the most important parasitic diseases with serious social and economic impacts mainly in Latin America. Therefore Chagas’ disease treatment is still a challenge, mainly in Brazil, where the only commercially available drug is benznidazole (Rochagan®). Since 1984, the WHO has recommended the use of crystal violet (gentian violet) in blood banks in endemic areas to prevent transmission by transfusion.

An image-based QSAR approach, called Multivariate Image Analysis Applied to Quantitative Structure-Activity Relationships (MIA-QSAR) is described as a tool to model the toxicities of a series of organotin compounds against Aedes aegypti and Anopheles stephensi mosquito larvae, vectors of dengue and yellow fever. This methodology may help researchers to discover novel, potent mosquito controllers.

Toxoplasma gondii (T. gondii) is the most common cause of secondary central nervous system infection in immunocompromised persons such as AIDS patients. Since purine salvage is essential for T. gondii and for other parasitic protozoa, inhibition of this salvage should block parasite growth. T. gondii adenosine kinase (EC 2.7.1.20) is the major route of adenosine (purine nucleoside) metabolism in this parasite. Four-Dimensional Quantitative Structure-Activity Relationship (4D-QSAR) analysis was applied to a series of 41 inhibitors of T. gondii adenosine kinase. Optimized 4D-QSAR models were constructed by Genetic Algorithm (GA) optimization and partial least squares (PLS) fitting, and evaluated by the leave-one-out cross-validation method. Moreover, we have used docking approaches to study the binding orientations and predict binding affinities of some benzyladenosines with adenosine kinase.

There is a need for improved treatments for diseases including protozoan parasitic diseases, such as chagas, malaria, trypanosomiasis, leishmaniasis, onchocerciasis, schistosomiasis, filariasis, toxoplasmosis, cryptosporidiosis, filardiasis and giardiasis. The existing chemotherapy for these diseases is not sufficiently effective due to factors such as toxicity, drug resistance and different strain sensitivities. New chemotherapies are needed to help in the control and prevention of these parasitic diseases.