1D pharmacophores in P450 models

During the development of SMARTCyp 2 we realized something profound, site-of-metabolism in CYP2D6 and CYP2C9 can be modelled by reactivity and a simple 1-dimensional pharmacophore. Simply by measuring the distance from the atom of interest to the pharmacophore we get a good variable to use for correcting the energy with.

So how come this simple correction works? It is rather well known that cytochromes P450s are quite flexible. A homology model of CYP2D6 has been shown to be more reliable for site-of-metabolism prediction through docking than the crystal structure, indicating a flexible site. The CYP2C9 structure has also been shown to be able to take on multiple conformations. Hence, a structure based model will require many different conformations to give accurate description of the binding, whereas a non-structure based model (i.e. SMARTCyp) simply implicitly includes this flexibility by assuming that there are very few restraints on the rotation of the substrate. SMARTCyp only uses the relative distance (no. of bonds) to the center of the molecule as a small penalty to the reactivity to prioritize sites that are closer to the end of the molecule than the center.


For the implementation of 1D pharmacophores we devised SMARTS strings that match the pharmacophores of CYP2D6 and CYP2C9 that matches the pharmacophores of the isoforms (strings below from SMARTCyp 2.2).

CYP2D6: positively charged amines
$([N][CX3](=[N])[N]) //guanidine like fragment
$([N^3X3H0]([#6^3])([#6^3])[#6^3]),$([N^3X3H1]([#6^3])[#6^3]),$([N^3X3H2][#6^3]) // primary, secondary, tertiary amines bound to only carbon and hydrogen atoms, not next to sp2 carbon
                                

CYP2C9: carboxylic acids and their bioisosteres
$([O]=[C^2][OH1]) // carboxylic acid oxygen
$([O]=[C^2][C^2]=[C^2][OH1]),$([O]=[C^2][c][c][OH1]) // vinylogous carboxylic acids (e.g. ascorbic acid)
$([n]1:[n]:[n]:[n]:[c]1) // tetrazole 1
$([n]1:[n]:[n]:[c]:[n]1) // tetrazole 2
$([O]=[C^2][N][OH1]) // hydroxamic acid
$([O]=[C^2]([N])[N]) // urea
$([O]=[S][OH1]) // sulfinic and sulfonic acids
$([O]=[PD4][OH1]) // phosphate esters and phosphoric acids
$([O]=[S](=[O])(c)[C][C]=[O]),$([O]=[C][C][S](=[O])(=[O])[c]) // sulfones next to phenyls with carbonyl two bonds away
$([O]=[S](=[O])[NH1][C]=[O]),$([O]=[C][NH1][S](=[O])=[O]) // sulfones bound to nitrogen with carbonyl next to it
$([O]=[C^2][NH1][O]),$([O]=[C^2][NH1][C]#[N]) // peptide with oxygen or cyano group next to nitrogen
$([OH1][c]1[n][o,s][c,n][c]1),$([OH1][n]1[n][c,n][c][c]1),$([OH1][n]1[c][n][c][c]1) // alcohol on aromatic five membered ring
$([O]=[C]1[N][C](=O)[O,S][C,N]1) // carbonyl oxygen on almost conjugated five membered ring
$([O]=[C]1[NH1,O][N]=[N,C][N]1) // carbonyl oxygen on fully conjugated five membered ring
$([nD2]1[nD2][c]([S]=[O])[nD2][c]1),$([nD2]1[c]([S]=[O])[nD2][c][nD2]1),$([nD2]1[c]([S]=[O])[nD2][nD2][c]1) // nitrogens in histidine-like 5-ring with sulfoxide/sulfone next to it
$([O]=[SX4](=[O])[NX3]) // sulfonamides

References:
2D6 model
Patrik Rydberg and Lars Olsen "Ligand-Based Site of Metabolism Prediction for Cytochrome P450 2D6" ACS Med. Chem. Lett., 2012, 3, 69-73
2C9 model
Patrik Rydberg and Lars Olsen "Predicting Drug Metabolism by Cytochrome P450 2C9: Comparison with the 2D6 and 3A4 Isoforms" ChemMedChem, 2012, 7, 1202-1209

PhD fellowship in molecular drug research at the University of Copenhagen

The Faculty of Health and Medical Sciences, University of Copenhagen is pleased to announce that a PhD fellowship will be available from 1 September 2012 or as soon as possible thereafter. Applications are invited for the three-year fellowships from candidates that hold or expect to hold a master's degree in a field relevant to the following project:
The driving forces for recognition of drug compounds by cytochrome P450 enzymes - Computational chemistry studies on thermodynamics of binding. Supervisor: Associate Professor Lars Olsen, Department of Drug Design and Pharmacology (email: lo@farma.ku.dk).

An applicant with experience in computational chemistry (in particular molecular dynamics simulations), thermodynamic studies or protein-ligand studies will be preferred. Experimental experience with handling proteins will also be an advantage.

The project is part of the Faculty’ collaboration with the Leiden/Amsterdam Centre for Drug Research and are expected to lead to a double PhD degree at the University of Copenhagen and Vrije University Amsterdam (see press release).
The PhD student will spend a significant part of the time in Amsterdam, and fulfil the academic requirements for both Universities. In Denmark, the PhD fellowship is to be completed in accordance with the Ministerial order on the PhD programme at the universities (PhD order) from the Ministry of Science, Technology and Innovation and the Regulations and guidelines for the conferment of the PhD degree by the Faculty .

The terms of employment are stated in the agreement between The Danish Confederation of Professional Associations and the Ministry of Finance.

As an equal opportunity employer, the Faculty of Health and Medical Sciences invites applications from all interested candidates regardless of gender, age, ethnic origin or religion.
For further information, applicants may contact the main supervisor.

How to apply
STEP ONE: Make the following pdf-files:
Letter stating the interest and qualifications for the project (max. one page)
Full CV
Master's degree diploma (including grade transcripts for bachelor’s and master’s degrees)
Possible publication list
Possible references
Applicants with a Master's degree from abroad should also enclose a short description of the grading scale used.
STEP TWO: Apply on-line by filling in the application form below and uploading the pdf-files.

STEP THREE: Print the pdf-files and send one hard copy in an envelope marked “PhD September 2012 LACDR" to:
University of Copenhagen
Faculty of Health and Medical Sciences
Personnel Office
Universitetsparken 2
DK - 2100 Copenhagen
Denmark

The hard copy has to be received at the Faculty of Health and Medical Sciences, Personnel Office before the application deadline. Please do not send the application directly to the main supervisor, all applications should be sent to the Personnel Office.
Deadline for applications: Tuesday 17 July 2012 at 12 o'clock noon.
Evaluation process: Applications will be handled and processed by the main supervisor and by the Scholarship Committee. An answer as to the granting of the fellowship can be expected appr. 4 weeks after application deadline.