title: Targeting Pyrimidine Pathway of Plasmodium knowlesi: New Strategies Towards Identification of Novel Antimalarial Chemotherapeutic Agents.
abstract: OBJECTIVE
  Plasmodium knowlesi has been recently recognized as a human malarial parasite, particularly in the region of south-east Asia. Unlike human host, P. knowlesi cannot salvage pyrimidine bases and relies solely on nucleotides synthesized from de novo pyrimidine pathway. The enzymes involved in this are also unique in terms of their structure and function to its human counterpart. Thus, targeting Dihydroorotase, an enzyme involved in the pyrimidine biosynthesis, provides a promising route for novel drug development.
  
  
  METHODS
  The 3D structure of P. knowlesi Dihydroorotase was predicted, refined and validated. Multiple docking was performed and the resultant complex was used for 3D structurebased pharmacophore modelling. A combinatorial library of 2,664,779 molecules was generated and used for structure based virtual screening. The stability of resultant compounds was checked using simulation studies.
  
  
  RESULTS
  The modelled 3D structure of P. knowlesi Dihydroorotase enzyme is relaxed by running an MD simulation of 20 ns, and structure is validated by using Ramachandran plot and G-factor analysis. A five point based pharmacophore model was created and used as a query for screening in house database. The stability of two negatively charged compounds was studied, and ZINC22066495-DHOase complex was more stable throughout the simulation.
  
  
  CONCLUSIONS
  The present study shows that ZINC22066495 compound has a high potential for disrupting P. knowlesi DHOase enzyme and may be used as a potential lead molecule for effective pyrimidine biosynthesis inhibition in P. knowlesi.
authors.affiliation: Department of Bioinformatics, MMV, Banaras Hindu University, Varanasi, India.
authors.forename: Mayank
authors.initials: M
authors.lastname: Rashmi
authors.affiliation: Department of Biochemistry, Pt. J. N. M. Medical College, Raipur, India.
authors.forename: Manoj Kumar
authors.initials: MK
authors.lastname: Yadav
authors.affiliation: Department of Physics, MMV, Banaras Hindu University, Varanasi, India.
authors.forename: D
authors.initials: D
authors.lastname: Swati
mesh_terms: D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D003511:Cyclohexanols / Q000737:chemistry / Q000494:pharmacology*; D004080:Dihydroorotase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D057166:High-Throughput Screening Assays; D006801:Humans; D008958:Models, Molecular; D010755:Organophosphates / Q000737:chemistry / Q000494:pharmacology*; D021261:Parasitic Sensitivity Tests; D016790:Plasmodium knowlesi / Q000187:drug effects* / Q000378:metabolism*; D011743:Pyrimidines / Q000096:biosynthesis* / Q000737:chemistry
chemical_list: D000962:Antimalarials; D003511:Cyclohexanols; D004791:Enzyme Inhibitors; D010755:Organophosphates; D011743:Pyrimidines; C000624684:ZINC22066495; D004080:Dihydroorotase; C030986:pyrimidine
keywords: Docking; drug design; molecular dynamics simulation; pharmacophore; structure based virtual screening