Homology modeling come strumento computazionale nella progettazione di nuovi famraci: prospettive e

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Leishmania are human protozoan parasites (22)
transmitted by the bite Phlebotomine or Lutzomyia
sandfly vectors
All Leishmania species exhibit complicated life
cycles. Diseases Cutaneous (CL) and Diffuse
cutaneous (DCL) Mucocutaneous (MCL) Visceral
(VCL)
Existing drugs such as pentavalent antimonials,
pentamidine, Amphotericin B and Miltefosine are
toxic and associated with severe side effects and
resistance
NEW TARGETS FOR NEW DRUGS!!!
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Strategic direction for leishmaniasis research
Gathering informations.
Identify leishmanial CK1 gene (for example
lck1-lmc1, lck1-ldc1) using online databases
(GeneBank, GenAtlas, GeneCard, UniGene,
EntrezGene)
Identify protein lCK1 sequence and eventually its
isoform using Expasy database
Identify possible lCK1 roles in Leishmanias life
cycle through literature (for example
phosphorylatation of C3 and C3b) and collect
data from Protein-protein interactions databases
Collect all the compounds (small molecules) with
inhibitory effect
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Strategic direction for leishmaniasis research
From a Computational Chemistry point of view
From a Biochemistry point of view
Expression and purification of lCK1
Sequence analysis and alignment (blast, multalign)
Activity No
Pharmacophoric models using the ATP binding cleft
Biochemical essay with hCK1 inhibitors
Homology modelling strategy
Activity yes
Pharmacophoric models using existing inhibitors
Phosphoproteome analysis with bidimensional
electrophoresis and mass analysis
Virtual screening using free chemical databases
Protein-protein docking
New Leads
Far-Western blot Biacore
Ligand optimization
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Virtual screening
Molecular Docking
Pharmacophoric models based on known inhibitors
or binding cleft
Pharmacophoric model based on known inhibitors or
binding cleft
Final result
LipinskisRule of five
LipinskisRule of five
Virtual screening