e-LEA3D: ChemInformatic Tools and Databases
 
The following tutorial is also available in .pdf format tutorial.pdf

Here, we aim to find molecules that belongs to the molecular weight range [0 - 469], possess a carbonyl and a F sybyl atom type (= a fluorine ; see the pharmacophore property). The case is trivial but it allows the test to be rapidly executed. The de novo drug design is time consuming especially when the scoring function involves the docking program.

Note that the program uses a heuristic method and may not found an exact solution. Each run will produce a different solution.

All the parameters are already set: just press the button to reach the second step.

Define the docking function
  • PLANTS (12) docking program:

  • Protein structure file in AMBER pdb format (see help):  
  •  
  • Definition of the binding site around a residue or a ligand in the pdb structure:

    RESIDUE name   RESIDUE number   CHAIN (or leave empty)

    or give coordinates of the center of the binding site:

    x ,   y ,   z

    Binding site radius

    rq: water molecules are excluded in this online implementation.

  •  
  • Weight in final score
  •  

    Rq: the PLANTS score is given in the result html page along with the X-Score evaluation (13) of the binding mode indicated in parentheses.

  • Define the molecular-based function
  • Molecular properties (help ; Setting values are coming from drug-like and/or lead-like (narrower than drug-like) studies):

    Property nameMinimal valueMaximal valueWeight in final scoreReference for the setting values or property
    Molecular weight(1)
    XLogp(1) (8)
    Number of atoms (H excluded)(2)
    Number of h-donors(1)
    Number of h-acceptors(1)
    Polar solvent accessible surface area(3) (9)
    Volume(9)
    Area(9)
    Molecular Refractivity(2) (4) (10)
    Radius of gyration 
    Length 
    Moment of inertia Ixx(5)
    Moment of inertia Iyy(5)
    Number of rotatable bonds(2)
    Number of rings(2)
    Number of aromatic rings(2)

  • Similarity measure on fingerprint (11) using Ghose atom index vector of 120 cells (7):

    Tanimoto Tversky Minimal value Maximal value Weight in final score
     

    Reference molecule in .sdf format  

  • Lipinski rules: (6)

    If Yes, set the weight in the final score  
  • Molecular weight ≤ 500
  • Logp ≤ 6
  • Number of atoms ≤ 50
  • Number of hydrogen bond donors ≤ 5
  • Number of hydrogen bond acceptors ≤ 10
  • Chemical functions:

    If Yes, set the weight in the final score  

    List:

  • Searchable functions or atoms:

    C N O S P Cl Br F I acid ester carbamate amide amide-ter aldhehyde keto amine amine1 amine2 amine3 alcohol alcohol1 alcohol2 alcohol3 ether thiol carbonyl

    Definition: alcohol1: RCH2-OH ; alcohol2: R2CH-OH ; alcohol3: R3C-OH ; amine1: RNH2 ; amine2: R2NH ; amine3: R3N

    where R is a substituent (H excluded).

  • Pharmacophore:

    If Yes, set the weight in the final score  

    List:

    Syntax:

    [feature 1] [feature 2] [minimal distance] [maximal distance] ...

    Features: AH DH LIP AR 'Sybyl_atom_type'

  • AH (O N S F, except ether and thioether !)
  • DH (O-H, N-H, S-H)
  • sybyl mol2 atom type: { O.2, O.3, C.ar, C.3, C.2, C.1, N.3, N.2, N.1, N.ar, N.am, N.pl3, N.4, O.co2, S.3, S.2, S.o, S.o2, P.3, H, F, Cl, Br, I }
  • LIP (lipophilic center: substituant center or non-aromatic rings or fused-rings)
  • AR (aromatic center: aromatic fused rings (6-6, 6-5,.) or single ring 6 or 5 atoms))
  •  

    Help to set create a AMBER pdb format:

    In order to convert the .pdb structure file into a .mol2 file format required by PLANTS, the protein must be in pdb format as defined by AMBER program.

  • Use the PDBPQR server at http://www.nbcr.net/pdb2pqr/

  • Select the pdb ID code or upload your pdb file

  • Select AMBER options in "Pick a forcefield" and "Pick an output naming scheme"

  • Set the option "Add/keep chain IDs in the PQR file"

  • Launch the execution

  • Download the .pqr file and rename it with the extension .pdb. The protein has been protonated and formatted with AMBER naming scheme

  • Be careful, heteroatoms like ligands are removed. In such case and if needed (for example, in defining the binding site), copy the ligand coordinates from the original file at the end of the pqr.pdb file.

  • Docking example:
  • Input for PQR: 3H0A.pdb

  • Get the output from PQR and copy/paste the HETATM 9RA block from 3H0A.pdb in the downloaded file: 3H0A_pqr.pdb

  • The above docking form must be filled with:

    RESIDUE name= 9RA

    RESIDUE number= 500

    CHAIN name= A

    Binding site radius= 10

    Weight in final score= 1

  • Download the sdf format of the ligand 9RA: bexarotene.sdf in order to evaluate it (the form appear at the second step (html page after the submit))

  • Help to set molecular properties:

  • The final score is the sum of each selected property. The score is expressed in percentage (%) where each selected property contributes proportionally to its weight (ie. ∑(weighti) → 100% with i a selected property).

    Example 1: set the minimal value only
    Molecular weight100-1.0Means MW must be ≥ 100
    Example 2: set the maximal value only
    Molecular weight-4691.0Means MW must be ≤ 469
    Example 3: set the minimal and the maximal value with the same value
    Molecular weight1001001.0Means MW must be exactly 100
    Example 4: set the minimal and the maximal value with different values
    Molecular weight504691.0Means MW must be ≥ 50 and must be ≤ 469

  • References:
    (1) 90th percentile: Proudfoot et al., Bioorg. Med. Chem. Letters, 15, 1087-1090, 2005.

    (2) Lepre et al., DDT, 6(3), 2001.

    (3) Clark and Pickett, DDT, 5(2), 2000.

    (4) Ghose et al., J. Comb. Chem., 1, 55-68, 1999.

    (5) Akritopoulou-zanze et al., DDT, 12, 948-952, 2007.

    (6) Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J., Experimental and computational approaches to estmate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews, 23, 4-25, 1997.

    (7) Roche et al., Development of a virtual screening method for identification of frequent hitters in compound librairies, J. Med. Chem., 45, 137-142, 2002.

    (8) Wang R. et al., J. Chem. Inf. Comput. Sci., 37, 615-621, 1997.

    (9) Eisenhaber, F., Argos, P., Improved strategy in analytic surface calculation for molecular systems: Handling singularities and computational efficiency., J. Comput. Chem., 11, 1272-1280, 1993.

    (10) Viswanadhan,V.N., Ghose A.K ., Revankar,G.R. and Robins,R.K., J. Chem. Inf. Comput.Sci, 29, 163-172, 1989.

    (11) Willet P., Barnard J.M., Downs G.M., Chemical similarity searching. Journal of Chemical Information and Computer Sciences, 38(6), 983-996, 1998.

    (12) Korb O, Stützle T, Exner TE., Empirical scoring functions for advanced protein-ligand docking with PLANTS. J Chem Inf Model., 49(1), 84-96, 2009.

    (13) Wang R., Lab H. and Wang S., Further development and validation of empirical scoring functions for structure-based binding affinity prediction, Journal of Computer-Aided Molecular Design, 16, 11-26, 2002.



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