PROPOSAL

In Silico Study Of Proinhibition Of Dihydrofolate Reductase Using Pyrimethamine

[Name of the Institute]

In Silico Study Of Proinhibition Of Dihydrofolate Reductase Using Pyrimethamine

CHAPTER: 1 Introduction

Introduction

Malaria remains one of the most health threats in the world .It is a very common disease in tropical country and mostly affects children under the age of five .However the children who survive gradually develop immunity that protect them from severe malaria. Approximately one million Africans die from severe malaria. One third of world population are at the risk of malaria according to The World Health Organisation (Abdi, 1995, pp. 12).

Around 1960 Chloroquine resistant P.falciparumhas been reported and as a consequence 2-to 3- fold increase death in 1980s.The alternative effective drug at the time, was Pyrimethamine, although, after a year of implementation the drug resistant parasite also reported. Pyrimethamine is one of few effective drugs against two malaria strains, Plamodium falciparum (Pf) and Plasmodium vivax (Pv).Plamodium falciparum is responsible for most cases of death associated with malaria. Pyrimethaminetargets the synthesis of dihydrofolatereductase (DHFR)-thymilate in Plamodium falciparum. Dihydrofolatereductase (DHFR)-catalase several key steps in synthesis of purines, pyrimidines and some amino acids (Murray, 1957, pp. 121).

Problem Statement

DHFR plays a critical role in cell reproduction. Thus, by inhabiting the DHFR, DNA synthesis will be effectively blocked therefore leading to death of prokaryotes and unicellular eukaryotes like Plamodium falciparum and Plasmodium vivax.

Clinically remarkable class of inhibitors that target a variety of bacterial and eukaryotic pathogens, including the lethal strain of the malaria Plamodium falciparum are antifolates.

CHAPTER 2: LITERATURE REVIEW

The current known antimalarial antifolate, which is in the main line of defence against Plamodium falciparum, is thought to target two enzymes in the folate biosynthesis pathway of the parasite (scheme 1). Dihydropteroatesynthetase , which catalyses the synthesis of 7,8-dihyropteroate from a 7,8-dihydropterin derivative , is acted upon by the sulfonamide and sulfone drugs, while dihydrofolatereductase, which effects the reduction of 7,8-dihydrofolate to 5,6,7,8-tetrahydrofolate.It is targeted by a structurally diverse group of folate antagonists, of which Pyrimethamine and Proguanil are widely used antimalarial agents. Inhibition of these activities disrupts the constant supply of tetrahydrofolate cofactors required for key 1-carbon transfer reactions, including those critical for DNA synthesis. Pyrimethamine and Sulfadoxine drugs are generally used in combination as they inhibit parasite reproduction synergistically (Haber, 1981, pp. 51).

Both DHFR and DHPS have been extensively studied at the genetic and enzymatic levels, and specific arrays of point mutations in their coding sequences have been established as the principal means by which malarial antifolate resistance is acquired. A range of studies has demonstrated the causal link between the observed polymorphisms in both DHFR and DHPS, and parasite resistance toPyrimethamine and the Sulfadoxine drugs, respectively.

Study of the Plamodium falciparum dihydrofolatereductase (DHFR) from different parasites reveals the structural basis for differential susceptibility to these antifolate drugs.Parasites showa pair of mutations from Ala-16 to Val-16 and from Ser-108 to Thr-108 are resistant to cycloguanil (the active metabolite of proguanil). On the other handa single Asn-108 mutation confers resistance to Pyrimethamine. Significant cross-resistance to both drugs occurs in parasites ...