Isocitrate lyase (ICL) is a key factor for the maintenance of latent tuberculosis infection. ICL catalyses the first committed step of the carbon-conserving glyoxylate bypass, the reversible cleavage of isocitrate into succinate and glyoxylate. Since Mycobacterium tuberculosis(MTb) has no back-up mechanism that can take over the role of ICL once it is inhibited, the ICL enzyme is an attractive target for inhibition and discovery of anti-TB drugs. Structurebased pharmacophore generation has beenused here in virtual screening of database compounds andde novo evolution method was employed in subsequent hit optimization. Accordingly, the strucutre of ICL was modeled and a pharmacophore was generated based on the structure of the binding site. Subsequent pharmacophore-based screening of one million compounds yielded 17 hits with greater binding energies than that of the natural substrate. The derivative of each hit showed even much stronger binding affinities. Both set of original and modified hit compounds were evaluatedin silico for their ADME-Tox properties. The results showed that Ligands O (242372) and P (Amb9999830), and derivatives ofD (Compound2099M), E (Compound3796M), K (Compound556M), N (STOCK1N-12208M), and P (Amb9999830M) possess promising drug-like properties and can be pursued as leads in the search for novel antitubercular agents.