Drug repurposing based novel anti-leishmanial drug screening using in-silico and in-vitro approaches

Abstract

Visceral leishmaniasis is a neglected tropical disease and is mainly caused by L. donovani in the Indian subcontinent. The mitochondria genome replication in Leishmania spp. is having a very specific mechanism, and it is initiated by a key enzyme called mitochondrial primase. This enzyme is essential for the onset of the replication process and growth of the parasite. Therefore, we focused on the primase protein as a potential therapeutic target for combating leishmaniasis diseases. We started our studies molecular modeling and followed by docking of the FDA-approved drug library into the binding site of the primase protein. The top 30 selected compounds were subjected for molecular dynamics studies. Also, the target protein was cloned, purified, and tested experimentally (primase activity assays and inhibition assays). Some compounds were very effective against the Leishmania cell culture. All these approaches helped us to identify few possible novel anti-leishmanial drugs such as Pioglitazone and Mupirocin. These drugs are effectively involved in inhibiting the promastigote of L. donovani, and it can be utilized in the next level of clinical trials.

Communicated by Ramaswamy H. Sarma

Keywords:

• Visceral leishmaniasis
• drug repurposing
• molecular docking and dynamics simulations
• in vitro anti-leishmaniasis drug screening
• primase

Acknowledgements

Praveen Rai would like to thank DBT JRF fellowship DBT/JRF/15/AL/202 for Govt. of India. Hemant Arya thanks Indian Council of Medical Research, Govt. of India, for Research Associate (ISRM/11(35)/2019) fellowship. Authors thank Central University of Rajasthan and DBT, Govt. of India (BT/PR16224/NER/95/176/2015) for funding and facilities.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

Praveen Rai would like to thank DBT JRF fellowship DBT/JRF/15/AL/202 for Govt. of India. Hemant Arya thanks Indian Council of Medical Research, Govt. of India, for Research Associate (ISRM/11(35)/2019) fellowship. Authors thank Central University of Rajasthan and DBT, Govt. of India (BT/PR16224/NER/95/176/2015) for funding and facilities.