Skin dryness and xerosis are the most common clinical manifestations of different dermatological diseases. The results of research showed that the clinically recommended emolients targeted on skin hydration and recovery of epidermal lipid barrier aren’t sufficient in the treatment of skin atopic diseases and may make skin dryer. Meanwhile, it was established that expression of aquaporines 3 (AQP3) is related to the pathogenesis of atopic dermatitis, psoriasis, eczema, and vitiligo. AQP3 provide a transport of water, glycerol and molecules of natural moisturizing factor increasing the skin hydration, proliferation of keratinocytes and wound healing. Thus, our study was focused on a search of new molecules and investigation theirs biological activity to accelerate expression of AQP3 in skin epidermis. Using DiffDock computational modelling to predict affinity for skin AQP3, aloin and emodin from Aloe vera extract were chosen as new potential candidates. These natural molecules demonstrated a good affinity towards the active site of AQP3 with an estimated docking score from -6.2 kcal/mol to -7.7 kcal/mol. To improve the affinity and stabilize the structure, trimethylglycine was suggested as natural osmolyte. Thorough Phyto4Health modelling to predict the pharmacological properties, it was found that these molecules could have anti-psoriatic, anti-inflammatory, and immunosuppressant activities useful for the treatment of skin atopic diseases. Furthermore, it was shown that combination of Aloe vera extract and trimethylglycine in a mass ratio of 1:1 revealed a clear synergetic effect to increase AQP3 amount up to 2 times, with a ratio and dose-dependent manner. Thus, the combination of Aloe vera extract and trimethylglycine has a promising potential in the drug development and treatment of severe dermatological diseases.