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Linezolid is the first and only oxazolidinone antibacterial drug was approved in the last 35 years. It exhibits bacteriostatic efficacy against M. tuberculosis and is a crucial constituent of the BPaL regimen (Bedaquiline, Pretomanid, and Linezolid), which was authorized by the FDA in 2019 for the treatment of XDR-TB or MDR-TB. Despite its unique mechanism of action, Linezolid carries a considerable risk of toxicity, including myelosuppression and serotonin syndrome (SS), which is caused by inhibition of mitochondrial protein synthesis (MPS) and monoamine oxidase (MAO), respectively. Based on the structure toxicity relationship (STR) of Linezolid, in this work, we used a bioisosteric replacement approach to optimize the structure of Linezolid at the C-ring and/or C-5 position for myelosuppression and serotogenic toxicity. Extensive hierarchical multistep docking, drug likeness prediction, molecular binding interactions analyses, and toxicity assessment identified three promising compounds (3071, 7549 and 9660) as less toxic potential modulators of Mtb EthR protein. Compounds 3071, 7549 and 9660 were having the significant docking score of −12.696 Kcal/mol, −12.681 Kcal/mol and −15.293 Kcal/mol towards the Mtb EthR protein with less MAO-A and B affinity [compound 3071: MAO A (-4.799 Kcal/mol) and MAO B (-6.552 Kcal/mol); compound 7549: MAO A (> −2.00 Kcal/mol) and MAO B (> −2.00 Kcal/mol) and compound 9660: MAO A (> −5.678 Kcal/mol) and MAO B (> −6.537Kcal/mol) and none of them shown the Leukopenia as a side effect due to the Myelosuppression. The MD simulation results and binding free energy estimations correspond well with docking analyses, indicating that the proposed compounds bind and inhibit the EthR protein more effectively than Linezolid. The quantum mechanical and electrical characteristics were evaluated using density functional theory (DFT), which also demonstrated that the proposed compounds are more reactive than Linezolid. Communicated by Ramaswamy H. Sarma

Since the last 4 decades, Bedaquiline has been the first drug discovered as a new kind of anti-tubercular agent and received FDA approval in December 2012 to treat pulmonary multi-drug resistance tuberculosis (MDR-TB). It demonstrates excellent efficacy against MDR-TB by effectively inhibiting mycobacterial ATP synthase. In addition to these apparent assets of Bedaquiline, potential disadvantages of Bedaquiline include inhibition of the hERG (human Ether-à-go-related gene; KCNH2), potassium channel (concurrent risk of cardiac toxicity), and risk of phospholipidosis due to its more lipophilic nature. To assist the effective treatment of MDR-TB, highly active Bedaquiline analogs that display a better safety profile are urgently needed. A structure-based virtual screening approach was used to address the toxicity problems associated with Bedaquiline. Among the virtually screened compound, CID 15947587 had significant docking affinity (− 5.636 kcal/mol) and highest binding free energy (ΔG bind − 85.2703 kcal/mol) towards the Mycobacterial ATP synthase enzyme with insignificant cardiotoxicity and lipophilicity. During MD simulation studies (50 ns), the molecule optimizes its conformation to fit better the active receptor site justifying the binding affinity. The obtained results showed that CID15947587 could be a useful template for further optimizing the MDR-TB inhibitor. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-021-00086-x.