Research Inspiration
Malaria is one of the most widespread and prevalence endemic diseases caused by invasion on human body by the protozoa parasites of the class of Plasmodium, affecting 5% of the world's population at any one time.(1) The worldwide mortality rate was conservatively estimated to be 1 million per annum in 1990 report by the World Health Organization (WHO) (2) but a recent reviews indicates that malaria may result in several million deaths annually. (3) Plasmodium falciparum, the most severe plasmodium (4), has developed resistance to chloroquine (5-6), quinine, sulfa/pyrimethanine combination, and mefloquine(7). This led to the introduction of artemisinin and its derivatives which have more efficacy than all of the previous antimalarial drugs. In developing new drug it is needed several testing phases that take more than 12 years (8) and a lot of money before it can be approved for marketing. QSAR, first developed in 1962 (9), is one of the ways to save time and money in drug development because the bioactivity of expected compounds can be predicted by no need of syntheses and testing its bioactivity hence narrow down the number of sythesized compounds.

Research Rationale
Artemisinin (qinghaosu) is the antimalarial principle isolated by Chinese scientists in 1972 from the aerial part of Artemisia annua L. (10), a plant used in traditional Chinese medicine for over 2,000 years. This drug shows good and high activity against malaria parasite P.falciparum. (11) However, it is imparied by (a) its insolubility in both water and oil (12), (b) its poor efficacy by oral administration (13), (c) high rate of recrudescence in treated patients (13), and short plasma half-life (14-15) so these stimulated scientists to synthesize more soluble in either oil or water and effective derivatives by the formation of dihydroartemisinin (12), and its esterification or etherification to, for example, artesunate (16), artemether (17-19), arteether (20-22), artelinic acid, and arteflene (23). All these derivatives' antimalarial activity are comparable to or better than that of artemisinin. These compounds appear to be the most rapidly acting of all antimalarial compounds developed so far. (24) In a previous work (25), they reported structure-activity realtionships of only C-9 analogs of artemisinin and 10-deoxoartemisinin using Comparative Molecular Field Analysis (CoMFA). Their CoMFA model had fair predictive ability and examination of the steric and electrostatic fields revealed a week correlation with the peroxy moiety, which was disturbing in light of its known requirement for activity. Now in this work QSAR of artemisinin and its derivatives are performed by using CoMFA, semiempirical calculation and molecular surface comparison. In semiempirical method eletronic properties, surface area, volume, hydration energy, refractivity, polarizability, mass, and partial charge are calculated by using Hyperchem and Chemplus molecular modeling programs.

Research Objective

1. Construct models for the relation between properties and antimalarial activity of artemisinin and its derivatives.
   
2. Compare electrostatic potentials and molecular shape by superimposition method.
   
3. Prediction of the biological activity of some other artemisinin derivatives that will help us for synthesis new drugs.
   
4. Design new drugs based on the model optained.
   

Work Plan

1. Literature survey of artemisinin and its derivatives bioactivity.
   
2. Construct these structures approximately 50 compounds by molecular modeling program.
   
3. Optimize these structures with ab initio calculation on 3-21G and 6-31G** level with Gaussian 94 program and semiempirical calculation with Hyperchem program.
   
4. Compare their structures between the two methods to find out the suitable method.
   
5. From the method chosen , calculate their electronic properties and electrostatic potentials. Calculate some molecular properties with Chemplus program.
   
6. Investigate the molecular similarity on this set of compounds in order to find the common structure subunit.
   
7. Perform the Comparative Molecular Field Analysis (CoMFA).
   
8. Construct the model that related between properties and bioactivity by mean of statistical method.
   
9. Predict the activity of some other artemisinin derivatives.
   
10. Propose new active antimalarial drugs.
    

Research Place

1. Computational Unit Cell and Austrian-Thai Center for Computer Assisted Chemical Education and Research (ATC). Room 204, Chemistry Building 2, Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.
   
2. Department of Theoretical Chemistry,
   Institue of General, Inorganic, and Theoretical Chemistry,
   Innbruck University, Innsbrcuk, Austria.
   
3. Institute of Theoretical Chemistry, Vienna University, Vienna, Austria.
   

Research Equipment

Hardware	- Silicon Graphic Workstation - IBM Power Station 530H - Personal Computer 80486 , Pentium
Software	- Gaussian 94 Program - Sybyl Program - Hyperchem Program - Chemplus Program - SPSS Program - Graphics Software - Docking Software - Surface Comparison Software - ANACONDA , ASP of Oxford Molecular

Reference

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