Structure-Based Drug Designing and Identification

What is it about?

Heat shock proteins (HSPs) emerged as a therapeutic target and it was observed that inhibition of HSP70-1 plays a pivotal role in the management of psoriasis. In-silico investigation involving techniques like molecular docking and molecular dynamics (MD) simulation analysis was performed against HSP70-1. Further, anti-psoriatic activity of bioactive immunomodulatory compounds present in ethanolic extract of Woodfordia fruticosa flowers (Wffe) using combination of bioinformatics together with ethnopharmacological approach has been explored in this study. Myricetin (- 8.024), Quercetin (- 7.368) and Ellagic acid (- 7.311) were the top three compounds with minimum energy levels as well as high therapeutic value/ADMET as compared to currently available marketed anti-psoriatic drug Tretinoin (- 7.195). ADMET prediction was used to screen ligands for drug-likeness and efficacy. Further, biogenically Woodfordia fruticosa gold nanoparticles (WfAuNPs) were synthesized and characterized by UV-Visible Spectroscopy (UV-vis), Dynamic Light Scattering (DLS), Zeta Potential, X-Ray Diffraction (XRD) and High Resolution Transmission Electron Microscopy (HRTEM) techniques. Synthesized WfAuNPs observed in the size range of 10-20 nm and were used to develop WfAuNPs-Carbopol®934 ointment gel. Subsequently, the therapeutic efficacy of WfAuNPs-Carbopol® 934 was checked against 5% Imiquimod-induced psoriasis like skin inflammation. WfAuNPs-Carbopol® 934 was found to be exerting better therapeutic effect in reducing the mean DAI score (0.63 ± 0.08), serum cytokines (TNF-α, IL-22 and IL-23) levels along with reduced epidermal thickness, parakeratosis and marked decrease in the hyperproliferation of keratinocytes. Results of the study revealed that the WfAuNPs-Carbopol® 934 could be an effective alternative treatment for psoriasis in near future.

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Why is it important?

This study is based on structure-based drug designing to identify novel inhibitors from flowers of W. fruticosa targeted to HSP70-1 as suppressors for IMQ-Induced Psoriasis-like skin inflammation in mice. Studies involve the validation of efficient and specific combinatorial approach comprising of in-silico molecular modelling together with bio-nanotechnology followed by in vivo assessment. We found that Myricetin, Quercetin and Ellagic acid as the top three compounds highly active against the HSP70-1 protein as compared to the currently marketed anti-psoriatic drug Tretinoin. This study concludes that these polyphenolics compounds present in the flowers of W. fruticosa could acts as novel inhibitors of HSP70-1 for their further promising use as potential anti-psoriatic agents. Topical application of 1% WfAuNPs-Carbopol® 934 was found to be most effective in the alleviation of IMQ-Induced Psoriasis-like skin inflammation symptoms and lowers the serum cytokines levels. Our present investigation opens up new avenues to elucidate and unravel the structural and mechanistic insights towards the design and development of new drug candidate using structure-based drug designing approach.

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