The rise of drug-resistant Mycobacterium tuberculosis (Mtb) strains has driven the search for novel therapeutic targets beyond conventional anti-tubercular agents. One such promising target is the ClpP protease complex, composed of ClpP1 and ClpP2 subunits, which is essential for proteostasis and bacterial survival under stress. This study explores the molecular dynamics (MD) and activation mechanism of Mtb ClpP subunits by N-[(benzyloxy)carbonyl]-L-isoleucyl-L-leucine (ZIL), an N-blocked dipeptide activator. MD simulations (200-1000 ns) were used to analyze structural stability, ligand interactions, and domain dynamics of both subunits in active and inactive states. ZIL-bound simulations showed that ClpP1 and ClpP2 maintained structural integrity, with conserved ligand-proximal residues forming stable interactions, although ClpP2 exhibited more variable polar contacts. In contrast, ligand-free simulations (500 ns) revealed significant instability, particularly in the handle domain and S1 binding pocket, underscoring the stabilizing role of ZIL. A 1000 ns simulation, with ZIL placed away from its known binding site on inactive ClpP1, showed that the ligand approached its target site and triggered a conformational shift in the handle domain, an early allosteric response, even though it did not fully dock as observed in the crystal structure. Notably, the residues in proximity to ZIL were associated with the observed structural changes in the simulations. The resulting MD trajectories provide a continuous, atomic-level view of ligand-induced dynamics and early activation events. Conducted without prior mechanistic assumptions, this unbiased simulation highlights the potential of targeting allosteric activation mechanisms and offers valuable insight into the rational design of ClpP-based therapeutics against drug-resistant Mtb.

Telacebec (Q203) and lansoprazole sulfide (LPZS) are promising lead molecules in the development of new antitubercular agents. In this study, a series of 15 thiazole-acetamide derivatives (5a--5o) were rationally designed and synthesized through bioisosteric modification of the key pharmacophores of Q203 and LPZS. Among the synthesized derivatives, Compounds 5c and 5d exhibited the moderate activity against Mycobacterium tuberculosis (M. tuberculosis/Mtb) H37Ra, with minimum inhibitory concentration99 (MIC99) values of 16 and 32 & micro;g/mL, respectively. These compounds also demonstrated half-maximal inhibitory concentration (IC50) values of 1.84 +/- 1.05 & micro;M (5c) and 0.73 +/- 0.13 & micro;M (5d), comparable to the reference drug isoniazid (INH). Cytotoxicity studies in mouse fibroblast cells revealed Compounds 5c and 5d with high selectivity index values, indicating selective inhibition of M. tuberculosis with low cytotoxicity. Molecular docking and dynamics studies of 5c with the QcrB subunit of Mtb cytochrome bcc-aa3 supercomplex (PDB ID: 7E1W) revealed key interactions with the conserved residues Thr313 and Ala179, providing mechanistic insight into its antitubercular activity. Although Compounds 5c and 5d did not yet achieve MIC99 values comparable to reference drugs, they represent a promising scaffold for further optimization and development as antitubercular agents.

KRASG12D is a common cancer-driving mutation that fuels the progression of several aggressive cancers, particularly pancreatic, colorectal, and lung cancers. Despite its well-established role in tumor development, effective therapeutic options that directly target KRASG12D remain limited. In this study, a structure-based virtual screening strategy was employed to identify potential KRASG12D inhibitors. Molecular docking was used to screen a library of traditional Chinese medicine (TCM) compounds, followed by ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) profiling. The top five drug-like candidates were subjected to 200 ns molecular dynamics simulations and MM-GBSA binding free-energy calculations. Three selected compounds were further evaluated in vitro, among which Rubimaillin showed notable anticancer activity with IC50 values of 1.10 ± 0.12 µM and 2.07 ± 0.02 µM against MIA PaCa-2 and PANC-1 cell lines, respectively, while displaying low toxicity toward non-tumorous HEK-293 cells (CC50 = 38.92 ± 8.49 µM). Rubimaillin also significantly inhibited cell migration and modulated key oncogenic biomarkers, including reduced KRAS protein levels, downregulation of BCL2, SOX9, and LC3 gene expression, and upregulation of p53 expression. Overall, these findings suggest that Rubimaillin may represent a suitable candidate for further investigation as a KRASG12D-targeted anticancer agent and demonstrate the value of integrating computational screening with natural product-based drug discovery approaches.

The ClpP (caseinolytic protease proteolytic) complex of Mycobacterium tuberculosis is crucial for its survival and pathogenicity, making it a promising but still underexplored therapeutic target for tuberculosis (TB). The ClpP complex, formed by the stacking of ClpP1 and ClpP2 subunits, plays a critical role in maintaining protein homeostasis under stress conditions. Our research specifically focuses on the ClpP2 subunit, which is crucial for binding with the AAA+ chaperone, a prerequisite for the proteolytic activity of the complex. In this study, we employed a structure-based drug repurposing approach to prioritize candidate compounds, which were subsequently evaluated for their antimycobacterial activity in vitro. Molecular docking-based virtual screening was performed against the S1 pocket of the Mycobacterium tuberculosis ClpP2 subunit, the known binding site of the ClpP complex activator (PDB ID: 4U0G). Docked compounds were ranked based on binding affinity (kcal/mol), and the top-ranked 50 candidates were selected for further comparative analysis for their protein–ligand interactions with the activator, ZIL (Z-Isoleucine-Leucine) (Binding affinity = – 6.1 kcal/mol). Compared to the control compound, the two top hit candidates, namely, Losartan and Gliclazide, demonstrated higher binding affinities of –8.6 kcal/mol each. Molecular dynamics (MD) simulations confirmed the stability of these protein–ligand complexes. Subsequently, the in vitro screening against whole M. tuberculosis H37Ra strain using the microbroth dilution assay revealed the half-maximal inhibitory concentration (IC50) values of 26.36 ± 20.96 µM for Losartan and 1.34 ± 0.78 µM for Gliclazide, compared to Isoniazid (INH) with an IC50 of 0.13 ± 0.005 µM. Although Gliclazide exhibited moderate inhibitory activity and remained less potent than INH, its relatively low IC50 value and reproducible antimycobacterial effect underscore its potential as a repurposable candidate for further investigation and optimization.

Tuberculosis (TB), caused by Mycobacterium tuberculosis, re-mains a major global health challenge due to the rise of multidrug-re-sistant (MDR) and extensively drug-resistant (XDR) strains. The urgentneed for novel anti-tubercular agents has driven extensive research inheterocyclic scaffolds, with thiazole-based compounds emerging aspromising candidates. Thiazole-based compounds exhibit potent anti-tubercular activity by targeting key bacterial enzymes, disrupting cellwall synthesis, and interfering with essential metabolic pathways. Thi-azole ring compounds show significant biological activity due to theirversatile chemical nucleophilic and electrophilic reactivity. This reviewprovides a comprehensive analysis of the conventional and modern syn-thetic approaches for thiazole-scaffold-based anti-tubercular agents.Additionally, it explores structural and functional group modificationson the thiazole core and their impact on anti-tubercular activity. Recentadvancements in molecular modeling, hybrid molecule design, and me-dicinal chemistry strategies for optimizing thiazole derivatives are alsodiscussed. The insights presented in this review highlight the potentialof thiazole scaffolds in TB drug discovery and underscore the need forfurther medicinal chemistry, preclinical and clinical investigations to de-velop effective and safer TB therapeutics. 1 Introduction 1.1 Chemical Reactivity of the Thiazole Ring 1.2 Different Conventional Methods Used for the Synthesis of Substi-tuted Thiazoles as Anti-tubercular Agents 1.2.1 Hantzsch Thiazole Synthesis 1.2.2 Gabriel Synthesis 1.2.3 Cook-Heilbron Synthesis 1.2.4 Other Reported Methods 2 Small Molecule Inhibitors (SMIs) as Anti-tubercular Agents 2.1 Phenyl-thiazole Derivatives 2.2 Imidazo[2,1-b]thiazoles 2.3 Carbazolo-thiazole Derivatives 2.4 Thiazole-chalcone Derivatives 2.5 Bis-thiazole Derivatives 2.6 2,4,5-Trisubstituted Thiazole Derivatives 2.7 Hydrazine-thiazole Derivatives 2.8 Thiazolidinone Derivatives 2.9 Carboxamide-thiazole Derivatives 2.10 Benzothiazole Derivatives 2.11 Amino-thiazole Derivatives 2.12 Thiazole-thiadiazole Derivatives 2.13 Thiazole-coumarin Derivatives 2.14 Pyrazolyl-thiazole Derivatives 2.15 Sulfonyl-thiazole Derivatives 2.16 Summary of Anti-tubercular Targets in Section 2 3 Molecular Modeling Analysis 4 Challenges of Mutations and Future Perspectives 5 Recent Advances in Clinical Trials for Anti-tubercular Drug Development 6 Conclusion

Cancer, a complex and multifaceted group of diseases, is a leading cause of death worldwide. Cancer leads to uncontrolled cell growth and has the capacity to spread to nearby tissues. There are different approaches reported for cancer treatment. Notably, 25

The FOF1-adenosine triphosphate (ATP) synthase is a classical anti-tubercular target that has led to Bedaquiline (BDQ), marketed as Sirturo® in 2012 for the treatment of tuberculosis (TB). A co-crystal structure of BDQ bound within the c subunit of the rotary ring of Mycobacterium phlei FOF1-ATP synthase was reported in 2015. Meanwhile, a hypothesis was made for its potential binding at another site in the ε subunit of ATP synthase that needs further exploration. In view of the rapidly emerging drug resistance cases, a molecule targeting multiple sites of ATP synthase is highly desirable to cope with drug resistance. In fact, a thorough understanding of the FOF1-ATP synthase structure, various binding sites, and structural insights useful for the design of new potent inhibitors are much desired. Therefore, we performed a systematic assessment of the recently resolved structures of subunits c and ε of mycobacterial ATP synthase and explored the binding characteristics of few known potent FOF1-ATP synthase inhibitors at the BDQ binding site (i.e., rotary ring, subunit c) and the hypothesized druggable subunit ε site. At the subunit c site, we observed the importance of GLU65, TYR68, LEU63, and PHE69 amino acids of protein that were in direct or water-mediated contacts with the known inhibitors, e.g., the hydroxyl and NH groups of BDQ showed hydrogen bonding and salt-bridge interactions that corroborated well with the X-ray-based information. Alongside, other inhibitors fitted well at the subunit c site and showed a combination of hydrophobic and hydrophilic interactions similar to BDQ but with different affinities. On the other hand, at the subunit ε site, we delineated the novel potential binding characteristics of these known inhibitors. Here, in the case of subunit ε site 1, ARG26, GLU31, and ARG115 were found to be important residues that were involved in either H-bond or salt-bridge interactions. Overall, the structural insights gained in this study may be useful in the design of new small molecule inhibitors targeting these two sites of the mycobacterial F-type ATP synthase enzyme.

Tuberculosis (TB) remains one of the leading infectious diseases with a significant impact on morbidity and mortality worldwide. Mycobacterium tuberculosis (Mtb), the causative agent of TB, is highly dependent on the electron transport chain (ETC) pathway for the generation of energy. Mycobacteria opportunistically move to another site for energy generation if any of their ETC sites are inhibited by any drug. In this study, we aim to design and evaluate novel scaffolds as potential anti-tubercular agents targeting the inhibition of ATP synthase. Recently, an Amiloride derivative HM2-16F was reported as an anti-tubercular agent targeting the inhibition of Mtb ATP synthase. Using HM2-16F as template compound, a library of the novel compounds was generated and subjected to docking analysis against the mycobacterial F-type ATP synthase (PDB-ID: 4V1F). The designed new compounds were found to have optimal ADMET properties and predicted binding affinity comparable to Bedaquiline. The benzofuran ring of compounds 4, 5, and 11 showed π-π interactions with Phe69, whereas compound 5 formed hydrogen bond with Gly62 (backbone) and with Glu65. Furthermore, compounds 4 and 11 showed hydrogen bond interaction with Glu65. Further synthesis and biological evaluation of the designed compounds may lead to a potential drug candidate against TB.

The Toll-like receptor 4 (TLR4) signaling pathway plays a leading role in triggering proinflammatory responses by targeting lipopolysaccharide (LPS) molecules from different bacteria. Meanwhile, it is also expressed at higher levels in breast cancer cells than in normal breast tissue. After LPS binding, it initiates downstream signaling pathways that promote inflammation and cell apoptosis. Thus, targeting TLR4-LPS presents a promising dual therapeutic strategy for breast cancer treatment by not only inhibiting tumor growth but also reducing inflammation within the tumor microenvironment. To achieve this, the discovery of a new antiinflammatory agent is needed to reduce LPS-mediated cancer cell proliferation and migration. In this study, a series of 4-aminoquinoline-thiazolidinone hybrid analogs (4a-m) have been synthesized to explore their antiinflammatory as well as anticancer activity to find a new lead. Among them, 4e revealed the most promising antiinflammatory (IC50 = 2.38 ± 0.77 μM) as well as anticancer activity (IC50 = 3.26 ± 1.06 μM) in RAW 267.7 cell line and triple-negative breast cancer (TNBC) cell line, respectively. Further structure-activity relationship study followed by MD simulation analysis was carried out to identify probable binding residues of TLR4 which may play a significant role in developing antiinflammatory activity for promoting cell apoptosis in cancer cells.

The synthesis of stimulus–responsive hydrogel–based scaffolds has been extensively investigated for controlled drug delivery applications. This study focused on synthesizing alginate and chitosan–based scaffolds for potential use in releasing antibiotic antimycotic solution (AAS) drugs. The controlled release of AAS from AAS–loaded alginate–chitosan scaffolds was investigated under distinct temperatures viz. 37 °C, 25 °C, and 10 °C, labeled as scaffolds A, B, and C, respectively. Porosity assessment revealed consistent and substantial mean porosity percentage of 95.06 ± 2.01 % across all scaffolds. The lower temperature of 10 °C significantly contributed to a gradual and consistent cumulative release of 91.67 ± 1.47 %, compared to 37 °C (94.07 ± 1.89 %) and 25 °C (92.75 ± 1.51 %). The Korsmeyer–Peppas model exhibited high R2 values (0.98, 0.97 to 0.99) for scaffolds A, B, and C, indicating its suitability for describing the in–vitro release of AAS. Furthermore, the obtained release exponent values (0.60, 0.65, and 0.72 for scaffolds A, B, and C, respectively) suggest non–Fickian diffusion as the primary mechanism governing drug release. The release was also pH–dependent, with slower release at acidic (pH 3) and faster release under basic conditions (pH 8) due to varying swelling ratios. Evaluation of thermodynamic parameters viz. Ea, ΔG, ΔH and ΔS, using the rate constant of the Korsmeyer–Peppas model, revealed positive values of ΔH > 0 and ΔS > 0, indicating the prevalence of hydrophobic interactions in the release process.

This paper reports investigations in food waste hydrolysis using ternary approach that combines statistical optimization, ultrasound-assisted enhancement of hydrolysis kinetics, and molecular simulations that provide physical insight into the process. Initial optimization of hydrolysis parameters (Box-Behnken design) resulted in total reducing sugar yield of 263.4 mg/g biomass in 42 h. Sonication of hydrolysis mixture at 35 kHz at 20 % duty cycle yielded 4x reduction in hydrolysis time with 22 % enhancement in TRS yield (320 mg/g biomass). Analysis of GLCM's secondary structure through FTIR spectra deconvolution revealed significant changes induced by sonication. Sonication led to reduction in alpha-helix, and increase in random coil content. Molecular dynamics simulations unveiled majority of amino acid residues associated with GLCM binding pocket in alpha-helix and random coil regions. Consequently, sonication widened the binding pockets, facilitating easier transport of substrate and product. This effect translated into faster kinetics of enzymatic food waste hydrolysis.

EDITORIAL article Front. Drug Discov., 21 February 2024Sec. In silico Methods and Artificial Intelligence for Drug Discovery Volume 4 - 2024 | https://doi.org/10.3389/fddsv.2024.1381450

KRAS (Kirsten rat sarcoma viral oncogene homologue), the most common mutated protein in human cancers, is the leading cause of morbidity and mortality. Before Sotorasib (AMG-510) was approved for non-small cell lung cancer treatment in 2020, the oncogenic KRAS mutations were believed to be non-druggable. High-resolution X-ray crystal structures of GDP-bound KRAS mutants with and without inhibitor are resolved and deposited in the Protein Data Bank (PDB). Nevertheless, to develop inhibitors targeting oncogenic KRAS mutants, understanding the dynamics of protein conformations and respective binding sites is crucial. In the present study, multiple molecular dynamics (MD) simulations were conducted on wild-type and mutant KRAS structures to understand how G12C or G12D mutations lead to the stabilization of the active state and how KRAS inhibitors lock the mutated conformations in their inactive state. The study found that the guanosine diphosphate (GDP)-bound KRAS mutants, G12C and G12D, were locked in the inactive state, in terms of stability, when the KRAS inhibitors, AMG-510 and MRTX1133, respectively, bind to the respective Switch-II (S-II) pocket. Covalent inhibitor AMG-510 locked the inactive GDP-bound KRASG12C mutant more efficiently when compared to the non-covalent inhibitor MRTX1133. The Cα atom distance between key highly dynamic amino acids from P-loop, Switch-I, and Switch-II domains, lying within 4 Å of the inhibitor, were stable in the KRAS mutant with bound inhibitors (AMG-510 or MRTX1133), but were varying largely in the absence of any inhibitor throughout the microsecond simulation. According to the per-residue energy decomposition results, S-II amino acids in inhibitor-free KRASG12C and KRASG12D mutants showed larger variations in energy values as compared to AMG-510-bound KRASG12C and MRTX1133-bound KRASG12D, respectively. For example, the inhibitor-free KRASG12C exhibited larger variations in energy values in the S-II residues, namely, Thr58, Gln61, Glu63, and Arg68, as compared to the AMG-510-bound KRASG12C. The study found that the higher stability of AMG-510 in torsion angles was due to its covalent nature of binding to the KRASG12C mutant. The S-II amino acids, namely, Thr58, Glu63, and Arg68 remained stable in AMG-510-bound KRASG12C. The study showed that AMG-510 binding significantly stabilizes the amino acids surrounding it, surpassing that of MRTX1133. The insights gained in the present study is expected to be useful in the design and development of new KRAS-targeted drugs.

This paper reports investigations into the biodesulfurization process in a dual substrate system. The model system comprises dibenzothiophene (DBT) and 4,6-dimethyl dibenzothiophene (4,6-DMDBT) as substrates and microbial strains of Rhodococcus rhodochrous. Experiments were conducted for single and dual substrate systems using different combinations of concentrations. The experimental results were analyzed using mathematical models for competitive kinetics with self-inhibition and competitive kinetics with uncompetitive self- and cross-inhibition. In the concentration range of 50-150 ppm, the enzyme affinity (Monod constant) of 4,6-DMDBT (4.25-4.83 mM) is higher than that of DBT (4.83-6.13 mM). As compared to single substrate system, the biodegradation velocity of DBT reduced to a lesser extent (35-69 %) than 4,6-DMDBT (45-76 %) in dual substrate system. No inhibition (either self or cross) was seen for the present biodesulfurization system. Retardation of biodegradation velocities was higher for relatively larger contents of 4,6-DMDBT, plausibly due to a decrease in membrane fluidity and permeability.

Removing hydrogen sulphide (H 2 S) from decentralized biogas plants by local upgrading techniques may prove to be an economical option for biogas purification, particularly in rural regions. In the present study, readily available biomass viz. bamboo and banana peel were used to prepare biochar and employed for H 2 S removal from raw biogas produced via a 3 m 3 Deenbandhu model biogas plant. The physical and chemical properties of fresh and used biochars were compared using several analytical techniques such as pH, EDX, FESEM, FT-IR, and XRD. The highest, 89.2% and 87.7% of H 2 S were removed from the raw biogas using banana peel and bamboo biochar utilizing the packed bed system. Four kinetic models viz . pseudo-first-order, pseudo-second-order, intraparticle diffusion, and Elovich models were fitted to evaluate the kinetics of H 2 S adsorption on bamboo and banana peel biochar. Kinetic study exhibited that the H 2 S adsorption for both the biochars followed the pseudo-second-order kinetic model with R 2 = 0.99. The high potential of the adsorbents for H 2 S removal, the ease of availability of raw materials, the simplicity of fabrication and utilization method of the adsorbents renders it as a potential candidate for biogas desulphurization in small scale biogas plants installed at rural areas.

This study focused on the investigation of in-situ degradation of the pharmaceutical pollutant carbamazepine (CBZ) using a ternary hybrid advanced oxidation process (AOP) that combines hydrodynamic cavitation (HC), persulfate anions (S2O2 8 ), and photocatalysis (UV-C irradiation with ZnO/ZnFe2O4 particles). The activation of S2O2  8 anion to generate SO center dot 4 could be simultaneously achieved using HC, UV-C irradiation, and ZnO/ZnFe2O4 particles. The ternary hybrid AOP resulted in a significant CBZ degradation of 98.13 +/- 1.03 %. The degradation profiles of CBZ were analyzed through a mathematical kinetic model derived from a network of chemical reactions. Experimental and simulated data were compared by adjusting the initial [Fe2+]/[H2O2] ratio as a controlled parameter. The optimal agreement between CBZ degradation data obtained from experimental and simulated was achieved for [Fe2+]/[H2O2] ratio = 10, elucidated significant leaching of Fe2+/Fe3+ ions from ZnO/ZnFe2O4 surface. The complimentary interactions among the individual AOPs, when applied simultaneously, were quantified using synergy index. The synergy index for the ternary system of HC + UV + ZnO/ ZnFe2O4 + Na2S2O8 was 4.46. The economic feasibility of the different HC-based hybrid AOPs was assessed through a comparison based on cavitational yield. The findings of this study have elucidated the potential of HC-based ternary hybrid advanced oxidation process for the effective oxidation of CBZ.

This study investigates sonophotocatalysis for the oxidation of Rhodamine B (RhB) dye using Zr doped ZnO nanoparticles. The synthesized nanoparticles were characterized by scanning electron microscope, Fourier-transform infrared, X-ray diffraction, Brunauer Emmett-Teller, thermogravimetric analysis, and photoluminescence. The hybrid sonophotocatalysis system achieved 98.73 ± 1.25% degradation of RhB under the conditions: RhB dye concentration = 10 ppm, 4 wt% of Zr doped ZnO = 0.1 g, reaction temperature = 30 °C, time = 60 min, pH = 7. A kinetic model was developed to predict the efficiency of RhB degradation through intrinsic elementary chemical reactions. The high coefficient of determination (R2 = 0.96) indicates the model's prediction accuracy in describing the degradation kinetics of RhB within sonophotocatalysis system. The electrical energy per order (EEO) analysis demonstrated that US + UVC + 4 wt% of Zr doped ZnO significantly reduced EEO (1055 kWh m-3 order-1). The synergy index for this combination was approximately 1.60, demonstrating a significant synergistic effect. Density Functional Theory (DFT) studies were utilized to propose the most probable degradation pathway, identifying reactive sites and potential byproducts. The simulations revealed the central carbon atom (1C site) as highly susceptible to radical attacks, indicating potential decolorization pathways such as N-de-ethylation, chromophore cleavage, and ring opening. Toxicity assessments of both the parent dye and its intermediates were conducted using ECOSAR (Ecological Structure Activity Relationship) to evaluate their ecological impacts. The combination of experimental results and kinetic modeling and simulations offers a deep understanding of RhB degradation complexities, driving advancements in sustainable water treatment technologies.