e-LEA3D: ChemInformatic Tools and Databases
 
  Please find 2 tutorials with an automatic test:

Virtual screening of commercial fragments extracted from FDA approved drugs


First step: Fill the scoring function form and Submit

Fill the following form to screen a database of molecules or to use the de novo drug design program.

The field "Weight in final score" must be different from 0 in order to activate the individual function.

Define the docking function
 PLANTS (12) docking program (see an example)
  • Protein structure file in pdb format (see Info):  
  •  
  • Definition of the binding site around a residue or a ligand in the pdb structure:

    RESIDUE name (case sensitive)   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 (e.g. 1)
  •  

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

    It is recommended to associate the docking function with an upper limit for the Molecular Weight (MW<500 for example) to speed up the run, particularly if you chose the de novo drug design option.

    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 score (e.g. 1)Reference for the property or for the setting values
    Molecular weightDrug-like (1)
    Lead-like if MW <= 350 (15)
    Fragment-like if MW <= 300 (Ro3; 16)
    XLogpDrug-like (1) (8)
    Lead-like if logP <= 3 (15)
    Fragment-like if logP <= 3 (Ro3; 16)
    Number of atoms (H excluded)Drug-like (2)
    Number of h-donorsDrug-like (1)
    Fragment-like if nhd <= 3 (Ro3; 16)
    Number of h-acceptorsDrug-like (1)
    Fragment-like if nha <= 3 (Ro3; 16)
    Polar solvent accessible surface areaDrug-like (3) (14) (9)
    Fragment-like if PSA <= 60 (Ro3; 16)
    Volume(9)
    Area(9)
    Molecular RefractivityDrug-like (2) (4) (10)
    Radius of gyration 
    Length 
    Moment of inertia IxxDrug-like (5)
    Normalized ratio: Ixx/Izz
    Moment of inertia IyyDrug-like (5)
    Normalized ratio: Iyy/Izz
    Number of rotatable bondsDrug-like (2)
    Fragment-like if rot <= 3 (Ro3; 16)
    Number of ringsDrug-like (2)
    Number of aromatic ringsDrug-like (2)

     Similarity measure on fingerprint (11) using Ghose atom index vector of 120 cells (7)
       The uploaded reference molecule will not change (neither the conformation nor the ionization state)
       The Tversky index highlights an embedding pattern if the molecule is a substructure of the reference

    Tanimoto Tversky Minimal value Maximal value Weight in final score (e.g. 1)
     

    Reference molecule in .sdf format  

     Lipinski rules (+ maximal number of atoms): (6)
    If Yes, set the weight in the final score (e.g. 1) 
  • Molecular weight ≤ 500
  • XLogp ≤ 6 (or Logp ≤ 5)
  • 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 (e.g. 1) 

    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 (e.g. 1) 

    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))
  •  

    Preparation of the protein file for PLANTS

    The program PLANTS needs a .mol2 protein file format thus our procedure automatically protonates the uploaded .pdb structure file by using the program PDBPQR with AMBER forcefield option. Then, the pdb file is converted into a .mol2 file format.
    Example of the protein used in the automatic test (pdb 3H0A):
  • The protein structure file is 3H0A.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 appears 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.

    (14) Veber, D. F.; Johnson, S. R.; Cheng, H. Y.; Smith, B. R.; Ward, K. W.; Kopple, K. D., Molecular properties that influence the oral bioavailability of drug candidates, Journal of Medicinal Chemistry, 45(12), 2615-23, 2002.

    (15) Teague S.J., Davis A.M., Leeson P.D. and Oprea T., The Design of Leadlike Combinatorial Libraries, Angew. Chem. Int. Ed., 38(24), 3743-3747, 1999.

    (16) Congreve M., Carr R., Murray C. and Jhoti H. A 'rule of three' for fragment-based lead discovery?, Drug Discov Today, 8, 876-877, 2003.



      Copyright © 2008-2017 Université de Nice Sophia-Antipolis CNRS - All rights reserved
      | Contact us |