Computational protocol: Discovery of Mycobacterium tuberculosis Protein Tyrosine Phosphatase B (PtpB) Inhibitors from Natural Products

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Protocol publication

[…] All compounds of the in house library have been previously published and fully characterized. Particularly, compounds studied in this work have been described elsewhere (abbreviations further used in this work are reported in brackets): trachypone (6016) and tetra-acetyl-trachypone (Ac3) [], Kuwanol E (KuwE) [], tetra-hydro-isosophoranone (M2H) and isosophoranone (M2) [], 1,3,8-trihydroxy-6-methyl-4,5,7-triprenylanthrone (PirIII) [], 4,2’,4’-trimethoxy-6’-hydroxy,3’-prenyl-3-geranyldihydrochalcone (59-triMe) [], 4-O-glucosyl caffeic acid (Caf) [], 1,3,8-trihydroxy-6-methyl-5,7-diprenyl-4-γ,γ’dihydroxyprenyl-anthrone (Δ3) [], α-cubebin (α-Cub) [], bufotenine CH3I (Buf-I) [], 4,2’,4’,6’-tetrahydroxy-3’-prenyl-3-geranyldihydrochalcone (Ega1) [], cynarin (Cyn) [] and hesperidin (Hesp) [] (chemical structures are reported in ). Most probable tautomeric and ionization states at pH = 7 ± 1 were predicted by the LigPrep application of the Maestro suite [], and those endowed with a normalized probability higher than 0.7 were retained in the final form of the library. Energy minimization was carried out with the OPLS2005 force field []. [...] Coordinates of the target receptor for structure-based molecular modeling were retrieved from the Protein Data Bank, under the accession code PDB ID: 2OZ5 []. This structure has been solved by X-ray crystallography at 2.00 Å resolution and represents the only PtpB structure in complex with a small molecular inhibitor which was available at the time of experiments. Coordinates of the protein-ligand complex were energy minimized with Amber11 in a box of explicit TIP3P water molecules (10 Å buffer), by using the ff99bsc0 force field for the protein and the GAFF force field for the OMTS ligand [,]. The MM-GBSA python script was used for calculating the delta energy of ligands binding to PtpB, by following a procedure already described [].Coordinates of the OMTS were then manually removed and such generated protein structure was used as target receptor during docking calculations with GOLD Program 4.1.2 []. The binding site was centered on the CD2 atom of Phe161 and included all PtpB atoms within 20 Å. The highest accuracy of the GOLD genetic algorithm (200%) was used for docking the unique library. The GoldScore function was used. The GRID program was used for probing the potential energy of interaction of the OH2 probe atom within the catalytic site of PtpB [,]. The Grid center was placed in correspondence of Tyr125 and was of 17.04, 14.40, 16.50 Å (x, y and z axes). Grid maps were then visualized with Ligandscout 3.0 from Inte:ligand []. […]

Pipeline specifications

Software tools LigPrep, LigandScout
Applications Drug design, Small-angle scattering, Protein structure analysis
Organisms Mycobacterium tuberculosis
Diseases Multiple Sclerosis, Tuberculosis
Chemicals Tyrosine