Comparative modeling of HGPRT enzyme of L. donovani and binding affinities of different analogs of GMP.
Hypoxanthine-guanine phosphoribosyl transferase (HGPRT; EC 2.4.2.8) is a central enzyme in the purine recycling pathway. Parasitic protozoa (Leishmania donovani) cannot synthesize purines de novo and utilize the salvage pathway to produce purine bases. Thus, this enzyme is targeted in drug discovery and development. The model of the monomeric L. donovani HGPRT showed that this enzyme is an α/β type protein with a PRTase type I folding pattern. Among all of the computationally screened compounds, pentamidine, 1,3-dinitroadamantane, acyclovir and analogs of acyclovir had higher binding affinities than the real substrate (guanosine monophosphate). Amino acids of HGPRT that are frequently involved in the binding of these compounds are Lys 66, Asp 74, Arg 77, Asp 81, Val 88, Tyr 182, Arg 192 and Arg 194. It is predicted that patients suffering from both HIV and visceral leishmaniasis (VL) may benefit if they are treated with acyclovir or pentamidine in conjunction with first-line antileishmanial therapies such as miltefosine and AmBisome.
BioMedical Informatics Division, Rajendra Memorial Research Institute of Medical Sciences, Agam Kuan, Patna 800007, India.
Md Yousuf
MY
Ansari
Manas Ranjan
MR
Dikhit
Ganesh Chandra
GC
Sahoo
Pradeep
P
Das
D000595:Amino Acid Sequence; D006157:Guanosine Monophosphate / Q000031:analogs & derivatives* / Q000378:metabolism*; D007041:Hypoxanthine Phosphoribosyltransferase / Q000378:metabolism*; D007893:Leishmania donovani / Q000201:enzymology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017386:Sequence Homology, Amino Acid; D013816:Thermodynamics
D006157:Guanosine Monophosphate; D007041:Hypoxanthine Phosphoribosyltransferase