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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 ( Ld HDAC). The regression analysis of VA by 24 hrs viability assay confirmed its activity against  Ld HDAC. 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  Ld HDAC. For  in-silico  study, the 3D structure of target  Ld HDAC was developed by homology modeling. Based on their  in-silico  activity, we shortlisted 13 VA derivatives having maximum affinity for  Ld HDAC 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  Ld HDAC 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  Ld HDAC. Hence, the current investigation presents a search for novel target specific drugs to aid the anti-leishmanial drug development. Communicated by Ramaswamy H. Sarma

journal of biomolecular structure and dynamics

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