In Silico Prediction of Drug–Drug Interactions Mediated by Cytochrome P450 Isoforms

Abstract

Drug–drug interactions (DDIs) can cause drug toxicities, reduced pharmacological effects, and adverse drug reactions. Studies aiming to determine the possible DDIs for an investigational drug are part of the drug discovery and development process and include an assessment of the DDIs potential mediated by inhibition or induction of the most important drug-metabolizing cytochrome P450 isoforms. Our study was dedicated to creating a computer model for prediction of the DDIs mediated by the seven most important P450 cytochromes: CYP1A2, CYP2B6, CYP2C19, CYP2C8, CYP2C9, CYP2D6, and CYP3A4. For the creation of structure–activity relationship (SAR) models that predict metabolism-mediated DDIs for pairs of molecules, we applied the Prediction of Activity Spectra for Substances (PASS) software and Pairs of Substances Multilevel Neighborhoods of Atoms (PoSMNA) descriptors calculated based on structural formulas. About 2500 records on DDIs mediated by these cytochromes were used as a training set. Prediction can be carried out both for known drugs and for new, not-yet-synthesized substances. The average accuracy of the prediction of DDIs mediated by various isoforms of cytochrome P450 estimated by leave-one-out cross-validation (LOO CV) procedures was about 0.92. The SAR models created are publicly available as a web resource and provide predictions of DDIs mediated by the most important cytochromes P450.

Nitazoxanide and azithromycin for the early treatment of COVID‐19: A multi‐spectroscopic, biochemical and computational drug–drug interaction study

“…Drug-drug interactions might occur at any one of the following three levels; that is, pharmaceutical, pharmacodynamics, and pharmacokinetic. Such interactions may also have modulated (e.g., increase or decrease) the drug pharmaceutical action [12]. In the current study, we have investigated the pharmaceutical interactions of NTZ and AZT.…”

Nitazoxanide and Azithromycin for the early Treatment of Covid-19: A Multi-Spectroscopic, Biochemical and Computational Drug-Drug Interaction Study

“…When multiple drugs co-administrated in pharmacy practice, their chances of interaction with other drugs are increased substantially, as a result of interaction the pharmaceutical action of the drug might be changed [12,31]. In order to validate this aspect, two drugs alone and their interaction complex were subjected for antibacterial and antibio lm activities against some major human pathogens.…”

Multidisciplinary Insights into the Structure–Function Relationship of the CYP2B6 Active Site

“…In silico methods may be useful for explaining in vitro results, but they are not always 100% accurate on their own (Salonen et al, 2003;Radloff et al, 2013;Dmitriev et al, 2021) as some favorable ligand binding events visualized with X-ray crystallography or molecular docking can be unproductive in vitro (Talakad et al, 2011;Kobayashi et al, 2014;Maldonado-Rojas et al, 2016). A complete in silico characterization of the CYP2B6 structure-function relationship is limited due to many variables influencing the CYP2B6-ligand binding/metabolism event (de Graaf et al, 2005).…”

“…Specifically, a surplus of in silico information concerning CYP2B6 such as its substrate/inhibitor characteristics (Wang and Halpert, 2002;Korhonen et al, 2007;Ekins et al, 2008;Wang et al, 2019b), 13 crystal structures (Table 1), active site amino acids (Supplemental Table 1 and Table 1), and plasticity (Shah et al, 2012;Wilderman and Halpert, 2012;Shah et al, 2018) has been elucidated. The techniques of quantitative structureactivity relationships (QSARs) (Wang and Halpert, 2002;Lewis et al, 2010;Dmitriev et al, 2021), homology modeling (Lewis et al, 1999;Bathelt et al, 2002;Lewis et al, 2002), X-ray crystallography (Gay et al, 2010;Halpert, 2011;Shah et al, 2018), and molecular docking (Niu Radloff et al, 2013;Maldonado-Rojas et al, 2016) have been pivotal in this endeavor. For a full view of the significant in silico work done with CYP2B6, we have compiled a historical table of CYP2B6 homology models (Supplemental Table 1) and a modern table of CYP2B6 crystal structures/molecular docking results (Table 1) with predicted active site residues around various ligands noted.…”