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