Multidrug-resistant tuberculosis has been resistant over more than two primary drugs (isoniazid and rifampin) resulted due to misuse and mismanagement which leads to administration of improper treatment regimens and failure to ensure that patients complete the whole course of treatment. Screening the library of MDR-TB antagonists against the bacterial strains can improve the pharmacological optimization compared over the primary drugs. In the present study, virtual screening has been introduced using surflex dock targeting mycobacterial metabolite (DNA Gyrase) virtually screened against chemical library of Rifampin and Isoniazid. Consequently, HtrA2 has been virtually screened against chemical library of ciprofloxacin, ofloxacin and moxifloxacin according to their bio affinity and analysed polypharmacological affects. Derivate of Ofloxacin (ZINCID_39383034) demonstrate better interactions with HtrA2 (PDBID_2PZD) and so on derivate of Rifampin (ZINC_ID85907485) demonstrate better interactions with DNA Gyrase (PDBID_3IFZ) following Lipinski’s rule of five and without any mutagenic, toxic or carcinogenic effects. Comparatively, analysing the binding patterns of derivates contrary to their primary drugs, inferred that docking score of the derivates have been significant than the primary drug and toxic level has been reduced in contrary to their primary drugs which has proved hints for the future design of new derivatives with higher potency and specificity.