Project Summary/Abstract
Malaria, an infectious disease caused by Plasmodium parasites, continues to pose a serious global
health problem. PfATP6, a calcium-transporting enzyme present in Plasmodium falciparum, has been
identified as a target for new antimalarial drugs. Therefore, specific and potent inhibitors of PfATP6 hold
promise as a new generation of antimalarial agents. They may also be of value as research tools for the
elucidation of the enzyme’s physiological roles. Only a few PfATP6 inhibitors are presently known and
most of them suffer from limitations due to their high structural complexity, restricting their availability. A
notable exception is a group of structurally simple phenolic compounds that were originally identified in
library screens. As they feature hydroquinone and naphthoquinone scaffolds, they can be synthesized
straightforwardly, which is a major advantage. The proposed project focusses on the design and
characterization of novel PfATP6 inhibitors, with initial focus on the hydroquinone/naphthoquinone
scaffolds. The long term goal of this research is to obtain a comprehensive understanding of the
interactions between PfATP6 and small inhibitory molecules at the molecular level. As a first step, the
objective of this proposal is to identify and characterize inhibitors that are good candidates for future
development. Preliminary data suggest that the development of new PfATP6 inhibitors based on the
targeted scaffolds is an achievable goal. To reach it, the following two Specific Aims will be pursued:
Aim 1: Establish the structural requirements for effective PfATP6 inhibition. An initial library of 50-
60 potential inhibitors will be obtained from vendors or be synthesized. These compounds will first be
evaluated in inhibition assays with purified PfATP6 and then in viability assays with living parasites. The
results will furnish structure-activity relationships that identify structural elements critical for inhibition.
Aim 2: Identify novel inhibitor scaffolds using structural models of the inhibitor binding site of
PfATP6. Applying computational techniques, structural models of the currently unknown inhibitor binding
site will be generated. After having validated the models, their predictive capabilities will be employed for
virtual screens of compound libraries to identify alternative inhibitor types. The ultimate goal is to increase
the structural diversity of the PfATP6 inhibitor pool by adding compounds with new scaffolds.
The proposed research is innovative because it will be the first to systematically explore small
molecule PfATP6 inhibitors by a combination of experimental and computational approaches. It is
significant as it provides fundamental information necessary to develop novel anti-malarial agents and
valuable new research tools. Moreover, the project will enable the PI to initiate and sustain a meritorious
research program at Sacramento State, engaging students from underrepresented minorities in a multi-
disciplinary drug design project.