Early Toxicity Screening and Selection of Lead Compounds for Parasitic Diseases

Abstract

Despite many advances made in disease mechanisms knowledge and drug discovery and development processes, the election of promising lead compounds continues to be a challenge. Efficient techniques are required for lead selection of hit compounds selected through in vitro pharmacological studies, in order to generate precise low cost throughput data with minimal amount of compound to support the right decision making. In this context, the selection of lead compounds with physicochemical parameters that will benefit orally bioavailable drugs are crucial for patients compliance and cost effectiveness, as well as for successful pharmacology. A concept based in Lipinski's rules point out the importance of analyzing these informations in early stages. A hepatocyte screening system may provide data on many processes such as drug-drug interaction, metabolite formation, drug toxicity and ADME profile of a hit. Drug-induced liver injury is the most frequent reason for the withdrawal of an approved drug from the market and hepatocytes have a central role in the metabolism of xenobiotics. Cytotoxicity screening assays can also give some information about toxicity early drug discovery process. A set of goals in lead compound selection must be shared between all areas involved so the chances of success can be improved in translational research.

Anti-Trypanosomal Bufadienolides from the Oocytes of the Toad Rhinella alata (Anura, Bufonidae)

“…Selectivity is a well-accepted parameter of the safety and pharmacological activity of a compound [ 28 ]. Bufadienolides from oocytes of R. alata were evaluated against kidney monkey Vero cells.…”

Design, synthesis and cruzain docking of 3-(4-substituted-aryl)-1,2,4-oxadiazole-N-acylhydrazones as anti-Trypanosoma cruzi agents

“…Docking positions were captured using the PYMOL v 0.99X program. 30,31 Figure 2. Superimposition of the highest ranked solution of N-acylhydrazones (stick model) in the binding site of TCC (ribbons model), as calculated by GOLD v. 4.0.…”

Patenting bioactive molecules from biodiversity: the Brazilian experience

“…A successful drug is a combination of drug-like properties and biological activity with tolerable toxicity. Poor pharmaceutical properties due to poor solubility, permeability and metabolic stability account for about 40% of compounds that fail to reach the market [31][32][33]. During the hit identification stage, chemical libraries from different origins can be screened over a defined target using high-through put methods.…”

“…A great range of methods are widely used in predictive and multi-mechanisms screens based on chemical libraries in search for drugs with therapeutic potential [33,40,41]. The goal of those procedures is to evaluate, with reasonable accuracy, the potential of a compound to become a drug.…”