Leishmania species are the causative agents for Leishmaniasis which is one of the neglected tropical diseases causing 70,000 deaths worldwide each year. Squalene synthase enzyme plays a vital role in sterol metabolism which is essential for Leishmania parasite viability. Therefore squalene synthase of Leishmania donovani is a therapeutic target to inhibit growth of parasite. The 3D model of Leishmania donovani Squalene Synthase (LdSQS) was generated by homology modeling and validated through PROCHECK, ERRAT, VERIFY3D and PROSA tools. Virtual screening of the protein was performed by AutoDock with reported inhibitor, E5700 and two natural alkaloids. Molecular interactions were explored to understand the nature of intermolecular bonds between active ligand and the protein binding site residues using UCSF Chimera and PLIP server. The reported inhibitor showed the best binding affinity (-9.75 kcal/mol) closely followed by Ancistrotanzanine B (-9.55 kcal/mol) and Holamine (-8.79 kcal/mol). Ancistrotanzanine B showed low binding energy and permissible ADMET properties. Based on the present study, homology model of LdSQS and Ancistrotanzanine B can be used to design inhibitors with antileishmanial activity.