Image_logo.bmp (1885 bytes) MOL ECULAR PR OPERTIES O PTIMIZATION PROJECT




Property-Based Drug design

The creation of stable predictable models for different properties and  activities.

Lipophilicity

1995 [1]:

logP= -0.22 +0.033 MV -0.99 SCa -0.13 SCd

n=38, r=0.964, s=0.37

where MV is molecular volume, Ca is free energy H-bond acceptor factor, Cd is free energy H-bond donor factor.

1997 [2]:

logP= -0.01+0.249 a -0.68 SCa

n=234, r=0.961, s=0.34

where a is molecular polarizability

2000 [3,4]

logP= 0.266 a -1.00 SCa(o)

n=2850, r=0.970, s=0.23

where Ca(o) is overall free energy H-bond acceptor factor

2001 [5]:

             N

logPi = S [((logPj  + 0.267(ai - a j) - 1.00 (∑Ca(o)i -∑Ca(o)j)]/N           

                   j=1

n=138, r=0.981, s=0.29, F= 3431

 

where index i indicates the compound-of-interest, index j indicates a near neighbor; and  N is the number of closely related structures used.

2002 [6]:

                    N

logPi = S [((logPj  + 0.267(ai - a j) - 1.00 (∑Ca(o)i -∑Ca(o)j)]/N           

                     j=1

n=10937, r=0.972

References:

  1.       Raevsky, O.A., Schaper, K.-J., Seydel, J.K., H-Bond Contribution to Octanol-Water Partition Coefficients of Polar Compounds, Quant. Struct.-Act.Relat., 1995, 14, 433.

  2.       Raevsky, O.A., Quantification of Non-Covalent Interactions on the Basis of the Thermodynamic Hydrogen Bond Parameters, J.Phys.Org.Chem., 10, 405-413 (1997).

  3.        Raevsky, O.A., Schaper, K.-J., Waterbeemd, H. and McFarland J.W., Hydrogen Bond Contributions to Properties and Activities of Chemicals and Drugs,  In  Molecular modeling and prediction of bioactivity; Guntertofte, K. and Jorgensen, F.S., Eds.;  Kluwer Academic/Plenum Publishers: New York, 2000, pp.221-227.

  4.        Raevsky, O.A., Trepalina, E.P., Trepalin, S.V., ibid, pp. 489-490.

  5.        Raevsky, O.A., Molecular Lipophilicity Calculations of Chemically Heterogeneous Chemicals and Drugs on the Basis of Structural Similarity and Physicochemical Parameters, SAR and QSAR in Environ. Res., 2001, 12, 367-381 (2001).

  6.        Raevsky, O.A., Trepalin, S.V., Trepalina, E.P., Gerasimenko, V.A. and Raevskaja, O.E., SLIPPER-2001 Software for Predicting Molecular Properties on the Basis of Physicochemical Descriptors and Structural Similarity, J.Chem.Inf.Comput.Sci., 42, 540-549 (2002).

 

Solubility in water

Vapours Solubility in Water

2003 [1]:

logLw=-0.052 a + 1.73 SCa(o) - 0.82 SCd

n=426, r= 0.922, rcv= 0.920, s=0.84

logLw=-0.031 a + 1.64 SCa(o) - 0.98 SCd - 1.39 HCA - 1.53 Amine - 0.78 CX3 + 1.71 Amide

-        1.05 Ether + 1.09 ArNO2 - 0.78 IHB

n=426,  r=0.964, q2=0.960, s=0.58

Liquid Solubility

1997, [2]:

log 1/S=-0.42 +     a -     SCa(o) +SCd

n=45, r=     , s=, F=

2000, [3]:

log 1/S=-0.42 + a - SCa(o) + SCd

n=142, r=, s=, F=

2003, [4]:

logS = 0.434 0.298 a  +1.090 SCa(o) +0.304½SCd½                                                      

n = 629  r = 0.947  s = 0.536   q = 0.945

logS = 0.514  -0.277 a  +0.884 SCa(o) +0.352½SCd½ +0.350 N(cycl) 1.221 I(alk)

          0.357 I(CX3) +0.237 I(base) 0.473 I(RCOOH) 0.727 I(HBintra)

 n = 629  r = 0.970  s = 0.408   q = 0.968

logS = 0.523  -0.274 a  +0.882 SCa(o) +0.318½SCd½ +0.400 N(cycl) -1.367 I(alk)

          -0.433 I(CX3) +0.225 I(base) -0.423 I(RCOOH) -0.558 I(HBintra)             

n = 787  r = 0.967  s = 0.467   q = 0.966

Solids Solubility

2000, [3]:

logS = -0.39 0.233 a  +0.65 SCa(o) +0.13½SCd½

n=70, r=0.937, s=0.38, F=159.0

2002, [5]:                                                      

             N

logSi = S [((logSj  - 0.275(ai - a j) + 0.96 (Cai -Caj) 0.27(Cdi -Cdj)]/N                          

                   j=1

n=42, r=0.931, s=0.48

 

References:

  1. Raevsky, O.A. and Schaper, K.-J, Analysis of water solubility data on the basis of HYBOT descriptors. Part 1. Partitioning of volatile chemicals in the water-gas phase system, QSAR Comb.Sci., 2003 (submitted).
  2. Raevsky, O.A., Quantification of Non-Covalent Interactions on the Basis of the Thermodynamic Hydrogen Bond Parameters, J.Phys.Org.Chem., 10, 405-413 (1997).
  3. Raevsky, O.A., Schaper, K.-J., Waterbeemd, H. and McFarland J.W. ., Hydrogen Bond Contributions to Properties and Activities of Chemicals and Drugs, In  Molecular modeling and prediction of bioactivity; Guntertofte, K. and Jorgensen, F.S., Eds.;  Kluwer Academic/Plenum Publishers: New York, 2000, pp.221-227.
  4.  Schaper, K.-J., Kunz, B. and Raevsky, O.A., Analysis of water solubility data on the basis of HYBOT descriptors. Part 2. Solubility of liquid chemicals and drugs, QSAR Comb.Sci, 2003 (submitted).
  5. Raevsky, O.A., Trepalin, S.V., Trepalina, E.P., Gerasimenko, V.A. and Raevskaja, O.E., SLIPPER-2001 Software for Predicting Molecular Properties on the Basis of Physicochemical Descriptors and Structural Similarity, J.Chem.Inf.Comput.Sci., 42, 540-549 (2002).

Intestinal  Absorption  in  Human.

Passively transported drugs

2000 [1]:

FA=1/(1+10 [5.05 - 0.36 åCa + 0.26 åCd)]                                                           

N=31, r=0.974, s=0.09, Q=0.959

2003:

FA=1/(1+10 [2.20 - 0.016 (WFEASA+WFEDSA)]                                                          

N=154, r=0.910, s=0.15 , F=738.5

where OFEASA and OFEDSA  are 3D H-bond descriptors (see HYBOT)

 

Drugs with possible different mechanisms  of absorption

2002 [2]:

FA=1/(1+10[(-log(FAnrs/(1-FAnrs))- 0.36Ca(drug-nrs)+ 0.26 Cd(drug-nrs)])           (23)

n=100, r=0.945, s=0.11, Q=0.943

References:

  1.        Raevsky, O.A., Fetisov, V.I., Trepalina, E.P., McFarland J.W and Schaper, K.-J., Quantitative estimation of drug absorption in humans for passively transported compounds on the basis of their physicochemical parameters,  Quant. Struct.-Act.Relat., 2000, 19, 366-374.

  2.        Raevsky, O.A., Schaper, K.-J., Artursson, P., and McFarland, J.W., A Novel Approach for Prediction of Intestinal Absorption of Drugs in Human Based on Hydrogen Bond descriptors and Structural Similarity,  Quant. Struct.-Act.Relat., 2002, 21, 402.