Are calculated log P values for some guanine derivatives by different computer programs reliable?

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Pharmacokinetics

Background:

• Lipophilicity, indicated by the octanol/water partition coefficient (log P), is crucial for drug absorption, distribution, metabolism, and excretion (ADME).
• Accurate log P determination is essential for predicting drug behavior and designing new therapeutic agents.
• Guanine derivatives are a significant class of compounds with various biological activities.

Purpose of the Study:

• To evaluate the reliability of commercially available computer programs for calculating log P values.
• To compare computational log P predictions with experimental values for guanine derivatives.
• To assess the suitability of computational methods for lipophilicity assessment in drug discovery.

Main Methods:

• Calculation of n-octanol/water log P values for guanine derivatives, acyclovir, deoxyaciclovir, and their acetylated forms using multiple computer programs.
• Experimental determination of log P values using the conventional shake-flask method.
• Comparative analysis of predicted versus experimentally determined log P values.

Main Results:

• Commercially available computer programs yielded unreliable log P values for the examined guanine derivatives.
• Significant discrepancies were observed between computationally predicted and experimentally determined log P values.
• The accuracy of computational log P prediction varied among the tested programs and guanine derivatives.

Conclusions:

• Current computational programs are not sufficiently reliable for accurate log P prediction of guanine derivatives.
• Experimental methods like the shake-flask method remain essential for precise lipophilicity assessment.
• Further development of computational algorithms is needed to improve log P predictions for complex molecules like guanine derivatives.