Evaluation of the inhibitory potential of Valproic acid against histone deacetylase of Leishmania donovani and computational studies of Valproic acid derivatives

Abstract

Valproic acid (VA) is a proven inhibitor of human histone deacetylases (HDACs). The homogenous HDAC has been associated with all major human parasitic pathogens and hence, it has been considered an attractive drug target for anti-leishmanial therapy. To assist in drug design endeavors for HDACs, an in-vitro study has been presented to investigate the VA inhibition on Leishmania donovani HDAC (LdHDAC). The regression analysis of VA by 24 hrs viability assay confirmed its activity against LdHDAC. Moreover, the toxicity of VA is also well documented. Thus, the in-silico experiments were also conducted to screen the non-toxic VA derivatives as anti-leishmanial drug candidates having potential as inhibitors of LdHDAC. For in-silico study, the 3D structure of target LdHDAC was developed by homology modeling. Based on their in-silico activity, we shortlisted 13 VA derivatives having maximum affinity for LdHDAC and identified four potential derivatives that can specifically bind to this protein. After that, these ligands were subjected to molecular dynamics simulation. These derivatives may be effective against L. donovani promastigotes since they followed Lipinski's RO5 and were non-toxic. Thus, screened derivatives can be considered as lead ligands for targeting LdHDAC and may be used as possible drug candidates to treat leishmaniasis and overcome the limitation of anti-leishmanial drugs. This is the first report of antileishmanial potential of VA and its derivatives targeting LdHDAC. Hence, the current investigation presents a search for novel target specific drugs to aid the anti-leishmanial drug development.

Communicated by Ramaswamy H. Sarma

Keywords:

• L. donovani
• HDAC
• Valproic acid
• VA derivatives
• molecular docking and simulation

Acknowledgments

The authors thank Dr. Kislay Sinha for providing the facility to conduct experiments in vitro and L. donovani (MHOM/IN/1983/AG83) cells. The authors also thank the Kumaun University and Soban Singh Jeena University for any kind of assistance which was helpful to complete this research work.

Disclosure statement

The authors have no conflicts of interest to declare.

Additional information

Funding

This work was supported and funded by the National Institute of Pharmaceutical Education and Research, Hajipur. The authors did not receive any other financial assistance while the work was conducted.