Generation of new inhibitors of selected cytochrome P450 subtypes- In silico study

Physicochemical and pharmacokinetic compound profile has crucial impact on compound potency to become a future drug. Ligands with desired activity profile cannot be used for treatment if they are char-acterized by unfavourable physicochemical or ADMET properties. In the study, we consider metabolic stability and focus on selected subtypes of cytochrome P450 - proteins, which take part in the first phase of compound transformations in the organism. We develop a protocol for generation of new potential inhibitors of selected cytochrome isoforms. Its subsequent stages are composed of generation and assess-ment of new derivatives of known cytochrome inhibitors, docking and evaluation of the compound pos-sible inhibition on the basis of the obtained ligand-protein complexes. Besides the library of new potential agents inhibiting particular cytochrome subtypes, we also prepare a graph neural network that predicts the change in activity for all modifications of the starting molecule. In addition, we perform a systematic statistical study on the influence of particular substitutions on the potential inhibition prop-erties of generated compounds (both mono-and di-substitutions are considered), provide explanations of the inhibitory predictions and prepare an on-line visualization platform enabling manual inspection of the results. The developed methodology can greatly support the design of new cytochrome P450 inhibi-tors with the overarching goal of generation of new metabolically stable compounds. It enables instant evaluation of possible compound-cytochrome interactions and selection of ligands with the highest potential of possessing desired biological activity.(c) 2022 The Author(s). Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology. This is an open access article under the CC BY license (http://creativecommons. org/licenses/by/4.0/).

Automated summary

Physicochemical and pharmacokinetic compound profile play a crucial role in determining the potency of a compound to become a future drug. In this study, the focus is on the metabolic stability and selected subtypes of cytochrome P450 proteins. A protocol for generating potential inhibitors of these cytochrome isoforms is developed, which involves the generation and assessment of new derivatives, docking and evaluation of compound inhibition, and the use of a graph neural network to predict activity changes. The methodology provides valuable support in the design of new cytochrome P450 inhibitors and enables instant evaluation of compound-cytochrome interactions.