Computational protocol: Chemoinformatic Identification of Novel Inhibitors against Mycobacterium tuberculosis L-aspartate α-decarboxylase

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Protocol publication

[…] Structural alignment of unprocessed and processed E. coli ADC structures by the use of Multiprot shows a root mean square deviation (RMSD) of 0.19 Å for 89 Cα atom pairs. This suggests that the unprocessed and processed ADC structures are highly similar. Thus, in preparation for virtual screening, unprocessed MtbADC (2C45) was modified to the processed form, in which Ser25 was substituted with a pyruvoyl group. The active site as well as conserved and functionally important residues were selected by structural alignment of the processed MtbADC with processed TthADC:fumarate and HpyADC:isoasparagine complex structures using Multiprot and visualized using PYMOL . As the active site is at a dimer interface, an appropriate dimer was prepared. The model was further refined by adding missing hydrogens, assigning proper bond orders, and was submitted to a series of restrained and partial minimization using the optimized potentials for liquid simulations all-atom (OPLS_AA) force field in the Protein Preparation Wizard of Schrödinger . [...] To identify inhibitors against the above processed MtbADC, flexible ligand based high-throughput virtual screening (HTVS) mode of Glide 5.5 was carried out using 333,761 molecules of commercially available ligands from the Maybridge (14,400 molecules; and Zinc [, including National Cancer Institute (hereafter NCI; 316,181 molecules) and the United States of America Foods and Drug Administration approved drugs (hereafter FDA; 3,180 molecules)] databases. Using the TthADC:fumarate crystal structure as a guide, fumarate was docked with processed MtbADC and the docking score was used as a reference to identify drug-like inhibitors. The Maybridge, NCI and FDA molecules, as well as fumarate, were prepared by accounting for missing hydrogens, possible ionized states, tautomers and low energy ring conformations using the Glide LigPrep application .A grid file was generated using the Receptor Grid Generation protocol with centroid at the active site of the enzyme. A scaling factor of 1.0 was set to van der Waals (VDW) radii for the atoms of residues that presumably interact with ligands and the partial atomic charge was set to less than 0.25. Ligands were then allowed to dock with the high throughput screening (HTVS) mode and all the obtained molecules were subjected to the Glide extra precision (XP) mode of docking, which performs extensive sampling and provides reasonable binding poses . At this stage, ligands were accepted only if: (i) they interacted with the residues that bind substrate analogs in the TthADC:fumarate and HpyADC:isoasparagine complex structures, and (ii) the binding affinity glide scores (G-scores) were better than the reference MtbADC:fumarate score. These ligands were further assessed for their drug-like properties based on Lipinski's rule of five and also the absorption, distribution, metabolism, excretion and toxicity (ADMET) properties, calculated with QikProp version 3.2 (Schrödinger) . In addition, the docking poses and structural properties of some of the known ADC inhibitors, phenylhydrazine (PubChem chemical database ID CID7516), L-cysteic acid (CID72886), Oxaloacetate (CID164550) and D-serine (CID71077), were compared with those of the selected drug-like molecules. As the active site of MtbADC is located at the interface of a dimer, the selected molecules were cross-verified by performing virtual screening against processed monomeric ADC. […]

Pipeline specifications

Software tools MultiProt, PyMOL, LigPrep, QikProp
Applications Drug design, Protein structure analysis
Organisms Mycobacterium tuberculosis, Homo sapiens
Diseases Neoplasms, Tuberculosis, Drug-Related Side Effects and Adverse Reactions
Chemicals Anserine, S-Adenosylmethionine