Is there a way to computationally predict the membrane permeability of small molecule protein inhibitors?
I am not looking for 'absolute' values. I need to figure out relative permeability of two molecules through cell membrane.
You can calculate the lipophilicity of compounds, the ALogP vaues with Discovery Studio 4.0 software. To assess the relation of this value with experimentally approved data go to our open paper:
https://www.nature.com/articles/srep21088
Yes, lipophilicity (as LogP or LogDx) is used to determine permeability. You can check the following resources for more details:
Di, L. and E. H. Kerns (2003). "Profiling drug-like properties in discovery research." Curr Opin Chem Biol. 7(3): 402-408.
Di, L., E. H. Kerns, et al. (2009). "Drug-like property concepts in pharmaceutical design." Curr Pharm Des. 15(19): 2184-2194.
Giaginis, C. and A. Tsantili-Kakoulidou (2008). "Alternative measures of lipophilicity: from octanol-water partitioning to IAM retention." J Pharm Sci. 97(8): 2984-3004.
Avdeef, A. (2003). Absorption and Drug Development-Solubility, Permeability, and Charge State. New York., Wiley-Interscience.
Giaginis, C. and A. Tsantili-Kakoulidou (2008). "Alternative measures of lipophilicity: from octanol-water partitioning to IAM retention." J Pharm Sci. 97(8): 2984-3004.
Giringer, K., H. U. Holtkamp, et al. (2018). "Analysis of ruthenium anticancer agents by MEEKC-UV and MEEKC-ICP-MS: Impact of structural motifs on lipophilicity and biological activity." Electrophoresis PMID: 29400408.
Grumetto, L., C. Carpentiero, et al. (2012). "Lipophilic and electrostatic forces encoded in IAM-HPLC indexes of basic drugs: Their role in membrane partition and their relationships with BBB passage data." European Journal of Pharmaceutical Sciences 45(4): 685-692.
All the best
I recomend ACD/Percepta software: http://perceptahelp.acdlabs.com/help_v2016/index.php/Absorption_Caco2
Most of my publications deal with prodrugs molecules and topical delivery. However what we discovered was that the molecules do not have to be prodrugs to obey certain rules. First, I assume you want to know how much or the two small molecules cross the membrane. Then the use of the term permeability is Wrong! Permeability, which sounds to me like you are really talking about permeability coefficients (P), was made popular because one could calculate a partition coefficient using soft ware and you knew the molecular weight so one could use some form of the equation originally developed by Potts and Guy for predicting transdermal delivery: log P (permeability coefficient) = X (a constant) + Y log K (partition coefficient between octanol and water) - Z MW (molecular weight), X, Y and Z were determined by regression analysis on a large database. The problem with these Potts-Guy (PG) type equations is that the result is in units of speed such as cm/hour. What I think you want to predict is flux (J) which is in units such as mole/(cm^2)(hour). That tells you how much is being delivered which is what you want to know because therapeutic results are based on how much material (mass) is delivered. An equation that does this is the Roberts-Sloan (RS) equation also originally developed for predicting transdermal delivery: Log J (flux) = X + Y log S (solubility) octanol + (1-Y) log S water - Z MW (molecular weight), X,Y and Z are as defined above and were determined by regression on a large database. If you do not have a large database, but do know the physicochemical properties of the molecules, you can look at the balance of the lipid (octanol) and water solubilities, and molecular weights to see which molecule will permeate the membrane to the greater extent. Just plug in a number such as 0.5 or 0.7 for Y and a number such 0.001 or 0.01for Z and see what you get. One does not need to know X if one is just trying to get a rough comparison. Note permeability and "to permeate" are not interchangeable. Papers on the development and use of the RS equation are: Pharmaceutical Research, 23(2006)2729-2747; International Journal of Pharmaceutics, 329(2007)25-36; International Journal of Pharmaceutics, 351(2008)92-103.
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