Abstract
Dihydrofolate reductase (DHFR) plays a vital role in the DNA synthesis by reducing dihydrofolic acid to tetrahydrofolic acid which is an essential component. Synthetic ligands like methotrexate (MTX), aminopterin (AMP) and their analogues act as potential anti metabolites by mimicking the coenzyme dihydrofolic acid (DHFA) they inhibit the activity of DHFR antagonistically. Several ligands which are similar to MTX analogues and 6, 8 substituted 2 – naphthyls (NAP) which can mimic the pteridyl group of DHFA have been computationally designed. These ligands were proposed to hinder the formation N5, N10 methylene tetrahydrofolic acid (THFA) coenzyme, which is essential for the DNA synthesis. The docking studies were done using grid, generated with the 0.9 Vander Waals scaling for non polar bonds in the active site of the receptor. These newly designed ligands such as 14 ‐21 ,23 and 28 have shown good docking scores and predicted activities when compared to already existing ligands MTX and its analogues.
Highlights
The therapeutic effect of the clinical drug will be effective if the biochemical pathway of the enzyme can be exploited
Dihydrofolate reductase (DHFR) enzyme plays a vital role by catalyzing the biosynthesis of nucleotide (DNA)
THFA formed picks up one carbon unit from l-serine and is converted to coenzyme N5, N10 methylene tetrahydrofolic acid (THFA) where CH2 group bridges N5and N10 tetra hydrofolate[1]
Summary
The therapeutic effect of the clinical drug will be effective if the biochemical pathway of the enzyme can be exploited. THFA formed picks up one carbon unit from l-serine and is converted to coenzyme N5, N10 methylene tetrahydrofolic acid (THFA) where CH2 group bridges N5and N10 tetra hydrofolate[1] This coenzyme is utilized by thymidylate synthase for the synthesis of DNA. In this process the hetero cyclic ring, the methylene group at the 9th position and N10 methylated and demethylated aminopteridine play a vital role while undergoing reduction or formation of N5, N10 methylene tetrahydrofolic acid coenzyme. Taking these points into account several ligands similar to MTX analogues having different substituents were designed computationally. Designed ligands along with the existing MTX analogues were prefiltered for their drug like properties (ADME properties) before docking them into DHFR receptor active site i.e. Ile[7], Glu[30], Gln[35], Asn[64], Arg[70], Val[115], Arg[121], and Thr[136]
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