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.

Bioisosteric modification of Linezolid identified the potential M. tuberculosis protein synthesis inhibitors to overcome the myelosuppression and serotonergic toxicity associated with Linezolid in the treatment of the multi-drug resistance tuberculosis (MDR-TB).

Dihydrofolate reductase (DHFR) is a crucial enzyme that maintains the levels of 5,6,7,8-tetrahydrofolate (THF) required for the biological synthesis of the building blocks of DNA, RNA, and proteins. Over-activation of DHFR results in the progression of multiple pathological conditions such as cancer, bacterial infection, and inflammation. Therefore, DHFR inhibition plays a major role in treating these illnesses. Sesquiterpenes of various types are prime metabolites derived from the marine sponge Dactylospongia elegans and have demonstrated antitumor, anti-inflammation, and antibacterial capacities. Here, we investigated the in silico potential inhibitory effects of 87 D. elegans metabolites on DHFR and predicted their ADMET properties. Compounds were prepared computationally for molecular docking into the selected crystal structure of DHFR (PDB: 1KMV). The docking scores of metabolites 34, 28, and 44 were the highest among this series (gscore values of −12.431, −11.502, and −10.62 kcal/mol, respectively), even above the co-crystallized inhibitor SRI-9662 score (−10.432 kcal/mol). The binding affinity and protein stability of these top three scored compounds were further estimated using molecular dynamic simulation. Compounds 34, 28, and 44 revealed high binding affinity to the enzyme and could be possible leads for DHFR inhibitors; however, further in vitro and in vivo investigations are required to validate their potential.

/pdf/unveiling-the-efficacy-of-sesquiterpenes-from-marine-sponge-eexonxr5.pdf

Unveiling the Efficacy of Sesquiterpenes from Marine Sponge Dactylospongia elegans in Inhibiting Dihydrofolate Reductase Using Docking and Molecular Dynamic Studies

COVID-19 infection is caused by endemic crown infection (SARS-CoV-2) and is associated with lung damage and severe immune response. Non-Structural Proteins are the central components of coronaviral transcription and replication machinery in SARS-CoV-2 and also stimulate mRNA cap methylation to avoid the immune response. Non-Structural Protein 16 (NSP16) is one of the primary targets for the drug discovery of coronaviruses. Discovering an effective inhibitor against the NSP16 in comparison with Sinefungin was the main purpose of this investigation. Binding free-energy calculations, computational methods of molecular dynamics, docking, and virtual screening were utilized in this study. The ZINC and PubChem databases were applied to screen some chemical compounds regarding Sinefungin as a control inhibitor. Based on structural similarity to Sinefungin, 355 structures were obtained from the mentioned databases. Subsequently, this set of compounds were monitored by AutoDock Vina software, and ultimately the potent inhibitor (PUBCHEM512713) was chosen. At the next stage, molecular dynamics were carried out by GROMACS software to evaluate the potential elected compounds in a simulated environment and in a timescale of 100 nanoseconds. MM-PBSA investigation exhibited that the value of binding free energy for PUBCHEM512713 (-30.829 kJ.mol-1) is more potent than Sinefungin (-11.941 kJ.mol-1). Furthermore, the results of ADME analysis illustrated that the pharmacokinetics, drug-likeness, and lipophilicity parameters of PUBCHEM512713 are admissible for human utilization. Finally, our data suggested that PUBCHEM512713 is an effective drug candidate for inhibiting the NSP16 and is suitable for in vitro and in vivo studies.Communicated by Ramaswamy H. Sarma.

Structural screening into the recognition of a potent inhibitor against non-structural protein 16: a molecular simulation to inhibit SARS-CoV-2 infection.

ABSTRACT Mycobacterium tuberculosis (Mtb), which causes tuberculosis (TB), is the world’s most successful pathogen. If it is to survive in phagosomes, the tryptophan biosynthetic pathway is essential. The α-subunit of tryptophan synthase (TRPS) executes the irreversible catalysis of indole-3-glyceral-3-phosphate to generate indole. The β-subunit catalyses the conversion of indole and serine to tryptophan. Targeting the TRPS α-subunit may, therefore, render the enzyme inactive. The crystal structure of α-subunit downloaded from the protein data bank (PDB: 5OCW) has gaps at the amino acid sequence positions in three places. We, therefore, retrieved the entire amino acid sequence of the protein from the UniProt and built a complete protein structure by adding the missing amino acids using a Modeller. The 3D model of the α-subunit was then used as the target to develop inhibitors for Mtb. We downloaded 58,699 natural products from the Maybridge database. After space filtering, molecular docking, molecular dynamic simulation and binding free energy calculation were done to develop inhibitors for the TRPS α-subunit. Out of the 18 compounds selected, five virtual hit compounds, namely MFCD00103482, MFCD00118123, MFCD04110719, MFCD01005315 and MFCD04112426, bind well to the TRPS α-subunit. These five potential inhibitors for Mtb will be taken for preclinical testing.

Virtual high-throughput screening: potential inhibitors for the mycobacterial α-subunit of tryptophan synthase



Tuberculosis (TB) has long been the major infectious cause of mortality, ranking higher than HIV/AIDS as the most common cause of death from a single infectious agent worldwide. The EchA6 target of mycobacteria plays a vital role in synthesizing an important component of the mycobacterial outer membrane. The failure of TB treatment has prompted the investigation of novel anti-tubercular drugs.



This study was aimed at blockage of Mycobacterium tuberculosis cell-wall synthesis via EchA6 inhibition to overcome resistance strain.



Over 3,000,000 compounds and GSK951A (positive control) were investigated as the inhibitors in this study. The GROMACS molecular dynamic package was used to analyze the protein-inhibitor complex's conformational changes under constant temperature and pressure. Also, umbrella sampling (US) was used for free binding energy (∆G) calculation.



Four compounds were chosen for the docking investigation. According to the MD analysis, the studied inhibitors demonstrated good stability and flexibility. According to ∆G obtained from US, the ∆G of GSK951A, ZINC11815220, ZINC67770050, ZINC55048326, and ZINC89700914 were -6.14 kcal mol-1, -5.25 kcal mol-1, -10.19 kcal mol-1, -8.55 kcal mol-1, and -8.37 kcal mol-1, respectively.



In conclusion, ZINC67770050 is recommended for further study in the laboratory. This investigation is an important starting point for discovering anti-tubercular drugs using EchA6 inhibition.


Early blockage of Mycobacterium Tuberculosis Cell-wall Synthesis via EchA\6 Inhibition to Overcome Resistance Strain: Insights from Umbrella Sampling Simulations

Folate antagonists are classified as important and valuable therapeutic agents against infection, neoplastic, and inflammatory diseases. Dihydrofolate reductase (DHFR) is a biological target of two well-defined folate antagonists, classical and non-classical inhibitors. DHFR catalyzes the reduction of 7,8-dihydrofolate to 5,6,7,8-tetrahydrofolate benefits of NADPH as a cofactor. With the point to recognize new chemicals to be utilized for further structure-based drug design, a collection of 67753 molecules including chemicals and natural products have been screened through the docking method from the Zinc Database. The high ranked compound with regard to methotrexate (MTX), resulted to be three compounds comprises of ZINC29236925, ZINC31169388, and ZINC01629864, which further investigated by molecular dynamics (MD) simulation, Poisson–Boltzmann surface area method (MM-PBSA) and QMMM calculations. PCA analysis revealed that upon inhibitor binding, the DHFR folding is changed. Our QMMM data suggested that a structure with ZINC ID of ZINC31169388 has a stronger interaction with DHFR active site and could be a favorable candidacy for biological assessment and additional advanced improvement. Furthermore, ADMET prediction illustrated that all physicochemical factors of ZINC31169388 are within the satisfactory span described for human treatment.

Structure-based virtual screening, molecular docking and dynamics studies of natural product and classical inhibitors against human dihydrofolate reductase

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Structure-based virtual screening, molecular docking and dynamics studies of natural product and classical inhibitors against human dihydrofolate reductase