engleski

QSAR of Retinoids and Evaluation of Biosimilarity by on-Targets and off-Targets Prediction, and ADMET Properties Related to Safety Profile

Molecular features and safety profile of different retinoids (n=18) classified into four generations (nonaromatic, monoaromatic, polyaromatic and pyranone derivatives) have been explored by correlation studies between computed molecular descriptors (MDs), topological indices (TIs), drug-likeness scores (dls) (www.molinspiration.com) and predicted ADMET toxicity parameters (ADMET PredictorTM, Simulations Plus, USA). Targets probabilities were evaluated based on combination of 2D and 3D similarity measures with known ligands using Swiss Target Prediction webserver. Significant linear correlations were found between MDs (Mr, natoms, TPSA) and TIs (H, F, X, Wp, Sz) (R = 0.8151-0.9903). Drug-likeness scores have been computed for nuclear receptor ligand- and enzyme inhibitor-likeness: NRL-dls = 1.02-1.13, 0.56-0.61, 0.19-0.92 and -0.36 while EI-dls = 0.56–0.58, 0.15–0.45, 0.07–0.38 and 0.17 for 1st, 2nd, 3rd and 4th generation, respectively). The following parameters were predicted: ADMET Risk from 1 (seletinoid G) to 9 (etretinate) ; CYP Risk from 0 (seletinoid G) to 3 (retinol) ; TOX Risk from 0 (tamibarotene and temarotene) to 3 (palovarotene) while TOX MUT Risk 1 was computed only for adapalene, tazarotene and seletinoid G. The results of targets prediction revealed expected retinoids on-targets, i.e., transcription factors: RAR- and RXR-alpha-, beta- and gamma-receptors with high probability (p=1) for all retinoids except for etretinate, motretinide, tamibarotene, mofarotene and seletinoid G (p=0). Targets such as mitogen-activated protein kinases, nonreceptor protein kinase 1 and 2, 5-hydroxytriptamine receptor, adenosine receptor A3 and ornithine decarboxylase were also revealed with high probability for nonaromatic retinoids, retinoic acid and isotretinoin, while adrenergic receptors 2A, 2B and 2C was revealed only for isotretinoin. Less significant probabilities (p=0.5) of other targets such as prostacyclin receptor, prostaglandin EP2- and D2 receptors were revealed as adapalene targets. Other differet targets, including protein tyrosine kinases, with p below 0, 45, were revealed mostly for members of 2nd to 4th generation. Predicted nonRAR and nonRXR targets could be considered as retinoid off-targets which contribute to their side effects. Novel interactions discovered may lead to the retinoid molecule being repositioned as a therapeutic treatment for its off-target's associated disease, added insight into the retinoid's mechanism of action, and/or added insight into the retinoid's side effects.

retinoids; on- and off-targets; drug-likeness; ADMET; toxicity

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