Drug Design and pH
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    Drug Design and pH Drug Design and pH Presentation Transcript

    • Drug Design and pH! Jan H. Jensen! Department of Chemistry! University of Copenhagen! http://propka.ki.ku.dk/~jhjensen! 1
    • Drug Design and pH! Getting the protonation state right
 on the ligand
 and the protein! The protonation state determines !Charge and hydrogen bonding properties ! 2
    • 3
    • pKa value => charge as a function of pH! 1q( pH ) = 1 + 10 pH − pKa 4
    • The protonation state determines charge and hydrogen bonding properties ! 1ACJ.pdb! 5
    • Determining pKa values for ligands! Experimental:! Spectroscopic feature vs pH! NMR Shift! pH! Computational: ! substituents Hammet-Taft rules pK a = pK model + ρ ! ∑ σi i PH+  P + H+ pK a = ΔGrxn!/ RT ln(10) 6
    • Ligand pKa prediction software
 using Hammet-Taft rules! Epik ! http://www.schrodinger.com/products/14/4/ ! Marvin! http://www.chemaxon.com/marvin/sketch/index.jsp! MoKa! http://www.moldiscovery.com/soft_moka.php ! ACD/pKa DB!http://www.acdlabs.com/products/phys_chem_lab/pka/ ! 7
    • Drug Design and pH!Getting the protonation state right
 on the ligand 
 and the protein ! The protonation state determines !Charge and hydrogen bonding properties ! 8
    • Standard pKa values for residues ! 9
    • Non standard pKa values for residues in proteins ! Picture of non-standard! Protonation state in active site! 10
    • Simple rules for pKa Predictions?! AH  A- + H+! pKa = 4.5!pKa = ΔGrxn/1.36! pKa = 4.8 - 0.3! pKa = 4.8 - 0.5 + 0.2! pKa = 5.0! pKa = 4.8 + 0.2! pKa = 4.8! 11
    • PropKa! pK a = pK a + ΔpK a model Desolv + ΔpK a + ΔpK a HB Chg-ChgModel pKa values: C-End=3.20, Asp=3.80, Glu=4.50, His=6.50, Cys=9.00, Tyr=10.00, N-End=8.0, Lys=10.50, Arg=12.50. PROPKA1: Li, Robertson & Jensen Proteins 2005! (PROPKA3: Olsson, Rostkowski, Søndergaard, Jensen JCTC 2011)! 12
    • pKa: Hydrogen Bonding! ! !∆pKa= -0.8 , if D < d1! ∆pKa= -0.8  (D-d2) / (d1-d2), if D < d2! ! !!∆pKa ! !∆pKa= 0.0, if D > d2! O F0 O H O D0.0 0.0 d1 d2 D (Å) Li, Robertson & Jensen Proteins 2005! 13
    • Example: Asp102 in RNase H1!N 15.5Å=443∆pKa= +0.43 Arg46 Asp148 -1.2015.5 Å +0.73 Arg46 Asp102 4.5 Å -1.20 -0.46 -2.40 -0.48 Asp102 Leu103 NLocal =13a ∆pKa= +0.91 b c pKa = 3.8 + 1.3 - 3.3 - 1.7 = +0.1! Exp = < 2.0 Li, Robertson & Jensen Proteins 2005! 14
    • Ca 20,000 hits last 12 months!Included in PDB2PQR and Vega-ZZ (*)! 15
    • 16
    • PROPKA-VMD interface! 17 Rostkowski, Olsson, Søndergaard, Jensen BMC Struct. Biol. 2011!
    • 12 14 (a) Asp /Glu (b) Cys 10 12 8PROPKA Prediction 10 PROPKA Prediction 6 8 4 6 2 0 RMSD = 0.7! 4 RMSD = 1.0! -2 N = 210! 2 N = 11! -2 0 2 4 6 8 10 12 2 4 6 8 10 12 14 Experimental pKa values Experimental pKa values 10 14 (c) His (d) Lys 12 8PROPKA Prediction 10 PROPKA Prediction 6 8 4 6 2 4 RMSD = 1.2! RMSD = 0.7! 0 N = 41! 2 N = 24! 18 0 2 4 6 8 10 2 4 6 8 10 12 14 Experimental pKa values Experimental pKa values
    • pKa values can change upon ligand binding! Kb0 P+L P·L pK a − pH c H+ H+ 1 + 10 Ka f Ka c K obs = K 0 b pK af − pH PH+ + L PH+·L 1 + 10 Kb+ ⎛ [PH + iL] ⎞ ⎛ [H + ] ⎞ ⎜ 1 + [PiL] ⎟ [PiL] ⎝ ⎠ ⎜1 + K c ⎟ 0 ⎝ a ⎠ + [PiL] + [PH iL] K obs = = = Kb [P][L] + [PH + ][L] [P][L] ⎛ [PH + ] ⎞ ⎛ [H + ] ⎞ ⎜ 1 + [P] ⎟ ⎝ ⎠ ⎜1 + K f ⎟ ⎝ a ⎠ 19
    • pKa values can change upon ligand binding! Implication number 1:! Inhibition constant is pH dependent! pK a − pH c 0 1 + 10 K obs = K b 1 + 10 pKa − pH f 20
    • pKa values can change upon ligand binding! Implication number 2:! Change in Ki wrt pH means ! change in protonation stateupon binding! ∂ log(K obs ) − = qc − q fq= 1 ∂pH 1 + 10 pH − pKa qfK obs = K 0 b qc 21
    • pKa values can change upon ligand binding! Implication number 3:! Docking score using static 
 protonation state must be corrected! ⎛ 1+ 10 pK ac − pH ⎞ ΔGb = −RT ln(K b ) − RT ln⎜ 0 pK − pH f ⎟ = ΔGb + ΔGb, pH 0 0 ⎝ 1+ 10 a ⎠ 22
    • pKa values can change upon ligand binding! Implication number 4:! ΔH measured by calorimetry will be 
 buffer dependent and must be corrected! ΔH corrected = ΔH obs − (qc − q f )ΔH ion ΔHion is ionization enthalpy of buffer! 23
    • Effect of Ligands: PROPKA 2.0!pK a = pK a + ΔpK a model Desolv + ΔpK a + ΔpK a HB Chg-Chg Atom typing! H-bond donor/acceptor! Charged groups! Ligand ionizable groups/pKmodel! PROPKA 2: Bas, Rogers & Jensen Proteins 2008! 24 PROPKA3.1: Søndergaard & Jensen, in progress!
    • xxx.pdb! PROPKA!xxx.pka new_xxx.pdb! edit! new_xxx.pdb! PROPKA! new_xxx.pka! pKmodel! Edit = ! new pKmodel or! new atom types! 25
    • 1K1L.pdb -> 1K1L.pka! pKa! pKmodel! 10.3! 12.0! 3.2! Experiment! new_1K1L.pdb! N29! new_1K1L.pka! C91! C25! 26
    • 27 Bas, Rogers & Jensen Proteins 2008!
    • Summary! Implications for docking! Protonation state of ligand can be estimated
 computationally!Protonation states of active site residues are not! always “standard”! Protonation states can change upon binding!In which case docking score must be corrected! 28
    • Questions Now?! Questions Later?! Leave a comment on!http://proteinsandwavefunctions.blogspot.com/2011/02/drug-design-and-ph.html! 29