Influence of stereoisomer of dispiro-1,2,4,5-tetraoxanes on their binding mode with heme and on antimalarial activity: molecular docking studies Somsak Tonmunphean, a, * Atchara Wijitkosoom a and Yuthana Tantirungrotechai b a Department of Chemistry, Faculty of Science, Chulalongkorn University, Patumwan, Bangkok 10330, Thailand b Department of Chemistry, Faculty of Science, Mahidol University, Rama 6 Road, Bangkok 10440, Thailand Received 13 October 2003; revised 1 March 2004; accepted 1 March 2004 Abstract—Based on the fact that different isomers may exhibit substantial distinct activities, quantum chemical calculations and automated molecular docking simulations were carried out for 13 dispiro-1,2,4,5-tetraoxane compounds, which experimentally exist as a mixture of several isomers, to elucidate the most probable isomer(s) responsible for their antimalarial activity. The results indicate significant effects of stereoisomer on the binding mode and the activity. Moreover, the antimalarial potency of each compound can be described by the docking results. Compounds 1, 2, 4, 5, 7, and 9 have the most probable isomers coordinate suitably with heme iron and hence they have high activities while the most probable isomer in compounds 3 and 8 could not bind appropriately to heme yielding only moderate activities. On the other hand, the steric hindrance in compounds 11–13 prevents an approach of heme iron to peroxide bonds resulting in a devoid of antimalarial activity. However, compounds 6 and 10 with iso- propyl substituents exhibit a different docking character, which is possibly caused by a limitation in molecular flexibility of the available docking technique. Our results can be used as a guideline for stereochemical control in synthesis process to improve drug’s potency. Ó 2004 Elsevier Ltd. All rights reserved. 1. Introduction Malaria is the most important tropical disease, which causes an extremely serious health problem in many developing countries worldwide. Around 40% of the world’s population in 100 countries are at risk and the disease is estimated to cause around 300–500 million illnesses and more than 1 million deaths each year. 1 One of the most crucial obstacles for eradicating malaria is a widespread resistance of malarial parasite to almost all chemotherapeutic agents. Therefore, it is very necessary to seek for new drugs that are effective against drug- resistant strains in order to combat and relieve this tremendous prevalence. Artemisinin (Fig. 1A) and its derivatives are only a group of antimalarial compounds with no clinical report of resistance. 2 Unlike the already resisted antimalarial agents that contain nitrogen atom, these compounds have an endoperoxide moiety as critical pharmaco- phoric functional group, which may result in different mode of action and hence effective against drug-resistant strains. Although these compounds have been widely used in many countries, the current situation of malaria is still not significantly improved. The main reason is that artemisinin compounds are very expensive for most patients who are poor people. Therefore, new effective antimalarial drug with lower price is urgently needed. Currently, researchers are focusing on compounds Keywords: Molecular docking; Antimalarial activity; Dispirotetra- oxane; Stereoisomer. * Corresponding author. Tel.: +66-2-218-7602; fax: +66-2-218-7598; e-mail: somsak.t@chula.ac.th O O O O O CH 3 CH 3 H CH 3 H H 1 2 3 4 5 6 7 8 9 5a 8a 10 11 12 13 12a 14 H 15 (A) Artemisinin O O O O 1 2 3 4 5 10 11 12 13 14 6 7 8 9 15 16 (B) WR 148999 Figure 1. Structure of (A) artemisinin and (B) dispiro-1,2,4,5-tetra- oxane WR 148999 with atom numbering. 0968-0896/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmc.2004.03.003 Bioorganic & Medicinal Chemistry 12 (2004) 2005–2012