Phytochemical investigation, structural elucidation, in silico study and anti-psoriatic activity of potent bioactive...

Psoriasis is a chronic autoimmune pathological condition characterized by hyperactivation of proinflammatory cytokines (IL-6, TNF-α, IL-17, IL-23, etc.). Severe drug-associated toxicities like hepatotoxicity and nephrotoxicity (Methotrexate), teratogenicity (Tazarotene), hypercholesterolemia (Cyclosporine) and hypercalcemia (tacalcitol), are the forefront challenges that demand an alternative approach for the treatment of psoriasis. In the present study, a natural lead molecule 'Betulin' (BE, lup-20(29)-ene-3b,28-diol) was isolated from Betula utilis and subsequently, structure-based molecular docking was employed to identify the molecular target for psoriasis. The computational analysis reflects better affinity of BE towards pro-inflammatory cytokine as compared to standard drugs. Apart from this BE shows a greater affinity towards the overexpressed Glut-1 receptor in comparison to standard drug Metformin (Met). Based on the in silico screening the isolated lead compound was further processed for the evaluation of anti-psoriatic activity via imiquimod (IMQ 5%) induced psoriasis-like skin inflammation model. In vivo screening models were characterized by different parameters (psoriasis area and severity index (PASI) scores, macroscopically and behavioral evaluation, splenomegaly, cytokine levels and histological changes) and compared among the experimental groups. The experimental finding reflects comparable results of PASI score, i.e., 57.14% and 61.9% recovery of test BE-solution (180 mg/kg) and standard Betamethasone di-propionate ointment (BD-oint.0.5 mg/g), respectively. Focusing on other parameters, BE shows relative results such as an enhanced macroscopically with behavioral conditions, reducing the expression of proinflammatory cytokine as well as restoring histological changes with that of BD. These findings suggest that BE-isolated phytoconstituents from Betula utilis could be a potential agent and a step closer to psoriasis treatment. HIGHLIGHTPsoriasis is a multifaceted, immunologically mediated disease consequences production of high levels of proinflammatory mediators and overexpression of Glut-1 transporters that trigger keratinocyte proliferation and inflammatory cascades.A Himalayan silver birch, Betula utilis (Bhojpatra) contains many steroidal terpenes which are responsible for various pharmacological activities that could be exploited in drug development in psoriasis.The computational analysis of BE reflects a better affinity toward the proinflammatory cytokines with their target receptors and indicates a satisfactory range with a slight deviation from Jorgensen and Lipinski's rule and possesses a significant drug choice for psoriasis.Preclinical findings of BE-solution (BE-sol) give a positive response towards IMQ-induced psoriasis-like skin inflammation model.[Figure: see text]Communicated by Ramaswamy H. Sarma.