Structure based drug design and fragment based approach to identify potential methotrexate analogues as dual inhibitors for management of psoriasis

Abstract

Psoriasis is characterized as chronic inflammatory disorder of skin having unregulated hyperproliferation and shedding of plaques. As per first line treatment methotrexate is the most widely used cytotoxic drug for psoriasis. It shows anti-proliferative effect with hDHFR while anti-inflammatory and immunosuppressive action is due to AICART. Serious hepatotoxic effects are recognized with long-term treatment of methotrexate. In this study, in silico technique is used in this work to find Dual-Acting Methotrexate-like molecules with increased efficacy and decreased toxicity. Structure-based virtual screening assisted by a fragment-based method against a library of chemicals that are similar to methotrexate revealing 36 and 27 potential inhibitors of hDHFR and AICART respectively. Further, based on dock score, binding energy, molecular interactions, and ADME/T analysis compound 135565151 was chosen for dynamic stability evaluation. Overall, these findings provided information on possible methotrexate analogues for the treatment of psoriasis that had lower hepatotoxicity.

Communicated by Ramaswamy H. Sarma

Keywords:

• Psoriasis
• hDHFR
• AICART
• methotrexate
• molecular dynamics
• hepatotoxicity

Acknowledgments

Authors are also thankful to NEON LABORATORIES LTD. for providing gift sample of Methotrexate IP (Batch No.-MT/F/21009). Grateful for computational support from BioEmbryo HPC cluster Centre for Development of Advanced Computing (C-DAC). Authors are also grateful to Central University of Rajasthan for providing licensed Schrodinger molecular modeling software.

Disclosure statement

The authors declare no competing interests.

Additional information

Funding

Authors are thankful for getting financial support in from BRICS, DST/IMRCD/BRICS/PILOTCall3/Nanodrug/2019.