title: Establishment of correlation between in-silico and in-vitro test analysis against Leishmania HGPRT to inhibitors.
abstract: Hypoxanthine Phosphoribosyltransferase (HGPRT; EC 2.4.2.8) is a central enzyme in the purine recycling pathway of all protozoan parasites. Protozoan parasites cannot synthesize purine bases (DNA/RNA) which is essential for survival as lack of de-novo pathway. Thus its good target for drug design and discovery as inhibition leads to cessation of replication. PRTase (transferase enzyme) has common PRTase type I folding pattern domain for its activities. Genomic studies revealed the sequence pattern and identified highly conserved residues that catalyzed the reaction in protozoan parasites. A recombinant protein has 24 kDa molecular mass (rLdHGPRT) was cloned, expressed and purified for testing of guanosine monophosphate (GMP) analogous compounds in-vitro by spectroscopically to the rLdHGPRT, lysates protein and MTT assay on Leishmania donovani. The predicted inhibitors of different libraries were screen into FlexX. The reported inhibitors were tested in-vitro. The 2'-deoxyguanosine 5'-diphosphate (DGD) (IC50 value 12.5 μM) is two times more effective when compared to guanosine-5'-diphosphate sodium (GD). Interestingly, LdHGPRT complex has shown stable after 24 ns in molecular dynamics simulation with interacting amino acids are Glu125, Ile127, Lys87 and Val186. QSAR studies revealed the correlation between predicted and experimental values has shown R2 0.998. Concludes that inversely proportional to their docked score with activities.
authors.affiliation: Pharmacoinformatics Department, National Institute of Pharmaceutical Education and Research (NIPER), Hajipur 844102, India; BioMedical Informatics Division, Rajendra Memorial Research Institute of Medical Sciences, Agam Kuan, Patna 800007, India.
authors.forename: Md Yousuf
authors.initials: MY
authors.lastname: Ansari
authors.affiliation: Biochemistry Department, Rajendra Memorial Research Institute of Medical Sciences, Agam Kuan, Patna 800007, India.
authors.forename: Asif
authors.initials: A
authors.lastname: Equbal
authors.affiliation: BioMedical Informatics Division, Rajendra Memorial Research Institute of Medical Sciences, Agam Kuan, Patna 800007, India.
authors.forename: Manas Ranjan
authors.initials: MR
authors.lastname: Dikhit
authors.affiliation: Pharmacoinformatics Department, National Institute of Pharmaceutical Education and Research (NIPER), Hajipur 844102, India; BioMedical Informatics Division, Rajendra Memorial Research Institute of Medical Sciences, Agam Kuan, Patna 800007, India.
authors.forename: Rani
authors.initials: R
authors.lastname: Mansuri
authors.affiliation: BioMedical Informatics Division, Rajendra Memorial Research Institute of Medical Sciences, Agam Kuan, Patna 800007, India.
authors.forename: Sindhuprava
authors.initials: S
authors.lastname: Rana
authors.affiliation: Biochemistry Department, Rajendra Memorial Research Institute of Medical Sciences, Agam Kuan, Patna 800007, India.
authors.forename: Vahab
authors.initials: V
authors.lastname: Ali
authors.affiliation: BioMedical Informatics Division, Rajendra Memorial Research Institute of Medical Sciences, Agam Kuan, Patna 800007, India. Electronic address: ganeshiitkgp@gmail.com.
authors.forename: Ganesh Chandra
authors.initials: GC
authors.lastname: Sahoo
authors.affiliation: Pharmacoinformatics Department, National Institute of Pharmaceutical Education and Research (NIPER), Hajipur 844102, India; BioMedical Informatics Division, Rajendra Memorial Research Institute of Medical Sciences, Agam Kuan, Patna 800007, India.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Das
mesh_terms: D000595:Amino Acid Sequence; D003001:Cloning, Molecular / Q000379:methods; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006153:Guanosine Diphosphate / Q000378:metabolism; D006157:Guanosine Monophosphate / Q000378:metabolism; D007041:Hypoxanthine Phosphoribosyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D007893:Leishmania donovani / Q000201:enzymology* / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
chemical_list: D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D006153:Guanosine Diphosphate; D006157:Guanosine Monophosphate; D007041:Hypoxanthine Phosphoribosyltransferase
keywords: Docking; FlexX; Leishmania; QSAR; rLdHGPRT