No abstract

Human African Trypanosomiasis (HAT), a disease that provokes 2184 new cases a year in Sub-Saharan Africa, is caused by Trypanosoma brucei. Current treatments are limited, highly toxic, and parasite strains resistant to them are emerging. Therefore, there is an urgency to find new drugs against HAT. In this context, T. brucei depends on glycolysis as the unique source for ATP supply; therefore, the enzyme triosephosphate isomerase (TIM) is an attractive target for drug design. In the present work, three new benzimidazole derivatives were found as TbTIM inactivators (compounds 1, 2 and 3) with an I50 value of 84, 82 and 73 µM, respectively. Kinetic analyses indicated that the three molecules were selective when tested against human TIM (HsTIM) activity. Additionally, to study their binding mode in TbTIM, we performed a 100 ns molecular dynamics simulation of TbTIM-inactivator complexes. Simulations showed that the binding of compounds disturbs the structure of the protein, affecting the conformations of important domains such as loop 6 and loop 8. In addition, the physicochemical and drug-like parameters showed by the three compounds suggest a good oral absorption. In conclusion, these molecules will serve as a guide to design more potent inactivators that could be used to obtain new drugs against HAT.

Protein kinase B (PKB ⁄ AKT) is an attractive therapeutic target in anticancer drug development. We have recently identified by docking-based virtual screening a low micromolar AKT-2 inhibitor. Additionally, the virtual screening hit represents a novel AKT-2 inhibitor scaffold. In this work, we discuss a structure-based design strategy toward the optimization of this hit. Following this strategy and using a herein validated docking protocol, we conducted the design of novel compounds with expected improved activity over the parent compound. The newly designed molecules have high predicted affinity for AKT-2; are synthetically accessible and are contained within the kinase-relevant property space.Key words: AKT, cancer, drug design, structure-activity relationships Abbreviations: HBA, hydrogen bond acceptors; HBD, hydrogen bond donors; IFD, induce-fit docking; MOE, molecular operating environment; MW, molecular weight; RB, number of rotatable bonds; SAR, structure-activity relationships; TPSA, topological surface area; XP, extra precision. The serine ⁄ threonine kinase B, also known as AKT, has several downstream targets that regulate a number of processes associated with cell growth, differentiation and division. AKT is frequently amplified and over-expressed in human cancer cells and its inhibition is a promising therapeutic approach for the treatment of cancers (1,2). There are three known subtypes, AKT-1 ⁄ PKBa, AKT-2 ⁄ PKBb and AKT-3 ⁄ PKBc. Each one is associated with different types of cancers. In particular, AKT-2 is amplified in pancreatic, breast and ovarian tumors. AKT-3 is over expressed in hormoneinsensitive breast and prostate cancers (1). Aberrations in AKT-1 are less common. AKT has an N-terminal pleckstrin homology domain, a hinge region, a central kinase domain, and a C-terminal region (3). The kinase domains have a large similarity of more than 85% and the binding pocket residues are the same (3,4). To date, small molecules targeting the ATP-binding site in the kinase domain, and allosteric inhibitors interfering with the pleckstrin homology domain function have been reported, among others (3-6). AKT inhibitors, either ATP competitors or compounds that interact with regulatory domains, have shown promising activity in cancer treatment. It is thought that subtype-selective inhibitors are needed for optimal efficacy with acceptable toxicity (1). However, it remains to be determined if subtype selective inhibitors have a larger therapeutic window over compounds that inhibit all three subtypes (4). For example, a pan-AKT inhibitor with nanomolar activity against the three subtypes has been evaluated as an intravenous agent in clinical trials in patients with cancer (7). Small molecules targeting the ATP-binding site have been reported. These include isoquinoline-5-sulfonamides (8,9), pyrazole (see below), (10) indazole (11) and aminofurazan analogs (7). Several of these inhibitors haven been developed using structure-based design techniques and are reviewed in Ref. (4). Despite the fact that some c...