Journal of Computer-Aided Molecular Design 17: 583–595, 2003. © 2003 Kluwer Academic Publishers. Printed in the Netherlands. 583 Computational studies of new potential antimalarial compounds – Stereoelectronic complementarity with the receptor C´ esar Portela a , Carlos M.M. Afonso a , Madalena M.M. Pinto a & Maria João Ramos b,* a Centro de Estudos de Qu´ ımica Orgânica, Fitoqu´ ımica e Farmacologia da Universidade do Porto – Faculdade de Farm´ acia, Rua An´ ıbal Cunha, 164, 4050-047 Porto, Portugal; b Requimte – Departamento de Qu´ ımica, Faculdade de Ciências, Universidade do Porto – Rua do Campo Alegre, 687, 4169-007 Porto, Portugal Received 22 April 2003; accepted in revised form 15 August 2003 Key words: antimalarial activity, DFT, docking, hematin aggregation, malaria, quantum mechanics, stereoelec- tronic properties, xanthones Summary One of the most important pharmacological mechanisms of antimalarial action is the inhibition of the aggrega- tion of hematin into hemozoin. We present a group of new potential antimalarial molecules for which we have performed a DFT study of their stereoelectronic properties. Additionally, the same calculations were carried out for the two putative drug receptors involved in the referred activity, i.e., hematin μ-oxo dimer and hemozoin. A complementarity between the structural and electronic profiles of the planned molecules and the receptors can be observed. A docking study of the new compounds in relation to the two putative receptors is also presented, providing a correlation with the defined electrostatic complementarity. Introduction Malaria is one of the major health problems in the world. It is estimated that 40% of the population of our planet is exposed to the disease, with a prevalence of the order of 300–500 million clinical cases and 2 mil- lion deaths each year [1, 2]. In addition, the available antimalarial drugs are losing their efficacy, due to the development of resistance by the parasite [3–5]. The continuing spread of drug-resistant malaria imposes a need for the search of new antimalarial compounds, which could constitute an alternative to the currently used drugs [3–5]. The malaria parasite has a limited capacity for de novo amino acid synthesis, needed to acquire some of these essential nutrients to survive. The essential amino acids are obtained from human hemoglobin proteolysis [6]. This digestion of hemoglobin re- leases the heme moiety, which oxidizes to hematin, also known as ferriprotoporphyrin IX (Figure 1) [6]. * To whom correspondence should be addressed. E-mail: mjramos@fc.up.pt Free hematin is toxic to the parasite, damaging cel- lular metabolism by inhibition of enzymes, causing the peroxidation of membranes and originating the production of oxidative free radicals in the acidic en- vironment of the digestive vacuole [6]. Lacking the heme oxygenase that vertebrates use for heme cata- bolism, plasmodial species detoxify by sequestering this by-product into a chemically inert crystal [6]. The product formed, hemozoin, is an aggregate of several units of hematin linked by carboxylate-iron(III) and carboxylate–carboxylate coordinated bonds [7–9]. The referred detoxification process can be used as a target for antimalarial therapy [10–12]. Several anti- malarial compounds interfere in this metabolical path- way by associating with a derivative form of hematin, avoiding the aggregation of this porphyrin [13–15]. The death of the parasite arises as a consequence of the toxicity of the free hematin [16–21]. The most likely is that the drug–receptor association occurs between the antimalarial molecule and one or several units of a μ-oxo-dimer of hematin [13–15, 22–26]. The hematin μ-oxo-dimer is a complex of two molecules of hem-