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Histone deacetylase 8 (HDAC8) is a member of class I histone deacetylases (HDACs) that catalyzes the deacetylation of both histone and non-histone proteins. Dysregulation and overexpression of HDAC8 are implicated in the development of various complex diseases, including cancer and neurodegenerative disorders. HDAC8 plays a significant role in cancer progression, contributing to cancer cell proliferation, metastasis, immune evasion, and drug resistance. The available HDAC8-targeting inhibitors suffer from poor target engagement and low tolerability, and demonstrate off-target toxicity due to limited selectivity, leading to adverse effects in patients, and thus urging for the identification and development of new molecules. Drug repurposing is a useful strategy for identifying useful drugs for predefined targets which can be exploited here for identifying promising drug molecules against HDAC8. This study involved an integrated virtual screening against HDAC8 using the DrugBank database to identify repurposed drugs capable of inhibiting HDAC8 activity. The process started by selecting the top 10 drug molecules based on their binding affinity. The drug profiling and biological function of selected molecules were then evaluated, showing anti-cancer and anti-neurological properties with a high probability of being active. Interaction analysis revealed crucial binding of radotinib and sertindole molecules with the HDAC8 protein. Both molecules showed higher binding affinity than reference inhibitor droxinostat. The elucidated molecules were further evaluated for 500 ns long-run molecular dynamics (MD) simulation with HDAC8. Structural deviation, compactness, folding behavior, hydrogen bonds analysis, and secondary structure content profiling revealed complex stability formed by HDAC8 and the selected compounds. Principal component analysis and Gibbs free energy calculations strongly recommend that both complexes were highly stable during the simulation. Overall, the results indicate that radotinib and sertindole can be promising candidates as HDAC8-targeting repurposed drugs against cancer and neuropathological conditions. [ABSTRACT FROM AUTHOR]

Identifying novel therapeutic agents is a fundamental challenge in contemporary drug development, especially in the context of complex diseases like cancer, neurodegenerative disorders, and metabolic syndromes. Here, we present a comprehensive computational study to identify potential inhibitors of SIRT1 (Sirtuin 1), a critical protein involved in various cellular processes and disease pathways. Leveraging the concept of drug repurposing, we employed a multifaceted approach that integrates molecular docking and molecular dynamics (MD) simulations to predict the binding affinities and dynamic behavior of a diverse set of FDA-approved drugs from DrugBank against the SIRT1. Initially, compounds were shortlisted based on their binding affinities and interaction analyses to identify safe and promising binding partners for SIRT1. Among these candidates, Doxercalciferol and Timiperone emerged as potential candidates, displaying notable affinity, efficiency, and specificity towards the binding pocket of SIRT1. Extensive evaluation revealed that these identified compounds boast a range of favorable biological properties and prefer binding to the active site of SIRT1. To delve deeper into the interactions, all-atom MD simulations were conducted for 500 nanoseconds (ns). These simulations assessed the conformational dynamics, stability, and interaction mechanism of the SIRT1-Doxercalciferol and SIRT1-Timiperone complexes. The MD simulations illustrated that the SIRT1-Doxercalciferol and SIRT1-Timiperone complexes maintain stability over a 500 ns trajectory. These insightful outcomes propose that Doxercalciferol and Timiperone hold promise as viable scaffolds for developing potential SIRT1 inhibitors, with implications for tackling complex diseases such as cancer, neurodegenerative disorders, and metabolic syndromes. [ABSTRACT FROM AUTHOR]

New Delhi metallo-β-lactamase-1 (NDM-1), expressed in different Gram-negative bacteria, is a versatile enzyme capable of hydrolyzing β-lactam rings containing antibiotics such as penicillins, cephalosporins, and even carbapenems. Multidrug resistance in bacteria mediated by NDM-1 is an emerging threat to the public health, with an enormous economic burden. There is a scarcity in the availability of specific NDM-1 inhibitors, and also a lag in the development of new inhibitors in pharmaceutical industries. In order to identify novel inhibitors of NDM-1, we screened a library of more than 20 million compounds, available at the MCULE purchasable database. Virtual screening led to the identification of six potential inhibitors, namely, MCULE-1996250788-0-2, MCULE-8777613195-0-12, MCULE-2896881895-0-14, MCULE-5843881524-0-3, MCULE-4937132985-0-1, and MCULE-7157846117-0-1. Furthermore, analyses by molecular docking and ADME properties showed that MCULE-8777613195-0-12 was the most suitable inhibitor against NDM-1. An analysis of the binding pose revealed that MCULE-8777613195-0-12 formed four hydrogen bonds with the catalytic residues of NDM-1 (His120, His122, His189, and Cys208) and interacted with other key residues. Molecular dynamics simulation and principal component analysis confirmed the stability of the NDM-1 and MCULE-8777613195-0-12 complex. The in vitro enzyme kinetics showed that the catalytic efficiency (i.e., kcat/Km) of NDM-1 on various antibiotics decreased significantly in the presence of MCULE-8777613195-0-12, due to poor catalytic proficiency (kcat) and affinity (Km). The IC50 value of MCULE-8777613195-0-12 (54.2 µM) was comparable to that of a known inhibitor, i.e., D-captopril (10.3 µM). In sum, MCULE-8777613195-0-12 may serve as a scaffold to further design/develop more potent inhibitors of NDM-1 and other β-lactamases. [ABSTRACT FROM AUTHOR]

A simple, eco-friendly four analytical methods were established by improving the selectivity through the application of mathematical processing of UV absorption spectra for concurrent quantification of chlorthalidone (CTL) and azelnidipine (AZE). The UV absorption spectra were recorded using environment-friendly ethanol (10% v/v) and were mathematically processed using simple software provided with a UV spectrophotometer. The analytes' peak amplitude was determined using zero-crossing point first derivative spectra and ratio first derivative spectra of CTL and AZE, which were measured at 238.5 nm and 239.5 nm for CTL and 272.1 nm and 342.1 nm for AZE, respectively. The peak amplitude difference was determined from the ratio spectra of CTL and AZE by measuring the peak amplitudes at 211.8 and 267.2 nm for CTL and 328.4 and 286.1 nm for AZE. Further, ratio spectra of CTL and AZE were converted into zero-order spectra by subtracting the constant followed by multiplication with divisor spectra, and the peak amplitudes were measured at 226.9 nm and 257.3 nm for CTL and AZE zero-order spectra, respectively. Further, validation results of all the four methods confirmed the accuracy and precision of the methods by displaying good recovery (98.37–100.34%) and percentage relative standard deviation (0.397–1.758%), respectively. Good linearity was observed in the range of 1–15 μg/mL for both analytes with less than a 1 μg/mL limit of quantification. Further, the greenness and whiteness of the methods were evaluated by recently proposed AGREEness, complexGAPI, and white analytical chemistry techniques. The proposed UV spectroscopic methods were environmentally friendly, safe, economic, and effective, hence, could be used for regular quality control study of a formulation containing CTL and AZE. [ABSTRACT FROM AUTHOR]

Background: For the treatment of diabetes mellitus type 2, a new formulation containing vildagliptin and remogliflozin was developed. A simple and rapid RP-HPLC method employing linagliptin as an internal standard was developed for quality control of this medicine. Methodology: Formulation analytes, including IS, were separated on a Zorbax C18 column with isocratic elution of acetonitrile and phosphate buffer (pH 5) 55:45 v/v at a flow rate of 1.2 mL/min. The experiment was carried out at room temperature and monitored at a wavelength of 210 nm. The approach was also validated in accordance with the ICH Q2 requirements. Results: The optimized HPLC approach revealed a satisfactory linearity in the concentration ranges of 10-60 µg/mL and 10-100 µg/mL for VIL and REM respectively, with good regression coefficient ( R2≥0.998). The average accuracy for VL and REM was 99.57 percent and 100.59 percent, respectively, with a low percentage relative error. The method's precision was proven by the low percentage relative standard deviation. Furthermore, a robustness assessment employing a Pareto chart generated using a three-level factor interaction study, a multivariate technique, demonstrated that minor changes in individual experimental conditions had no effect on the test results. Finally, the optimized HPLC method was effectively used to assess VIL and Rem from formulation simultaneously. Conclusion: The findings of an assay comparing a simple and rapid isocratic RP-HPLC method devised for the simultaneous quantification of VIL and REM to a previously published approach revealed no significant differences in the assay results. As a result, it might be utilized in any analytical laboratory for quality control of this formulation. [ABSTRACT FROM AUTHOR]

Background: An anti-diabetic formulation consisting of vildagliptin and remogliflozin was prescribed for better glycemic control. In the present study a simple, rapid derivative spectrophotometric methods were evolved to analyze these two analytes from the formulations. Methods: Two processed UV spectrophotometric methods were established by measuring the peak amplitude at zero-crossing of second derivative spectra of analytes. The second procedure comprehends the generation of zero - order spectra from the mixture of analyte spectra by division and multiplication by the pure analyte spectra to remove the effect of one of the analytes. Results: Both methods showed linearity concentrations in the range of 2-75 µg/ml for RGF and 2-50 µg/ml for VGT. The low LOD and LOQ found for RGF and VGT by both methods indicated the good sensitivity of the methods. The mean percentage recovery was 98.60 % and 100.78%, for RGF and 98.81 % and 99.15 % for VGT, with low percent relative error. The % RSD for intra and inter-day precision was less than ±2%. Finally, the planned methods were employed for the assay of the VGT and RGF from the medicine and the outcomes were matched with the reported methods. Conclusion: The assay results of the formulation were in agreement with the concentration of labeled amount and no significant difference was observed in the results when compared to the reported method. Hence, the anticipated procedures could be applied for the routine quality control of formulations consisting of VGT and RGF. [ABSTRACT FROM AUTHOR]

A rapid, synchronized liquid chromatographic method was established for the estimation of hydrochlorothiazide (HCZ), amlodipine (AMD), olmesartan (OLM), telmisartan (TEL), and irbesartan (IRB) in binary and ternary coformulations using the same chromatographic conditions. Five analytes were separated on a Zorbax C18 column using isocratic elution with a mobile phase consisting of acetonitrile, methanol, and 20 mM phosphate buffer (pH 3.5) in a ratio of 45:20:35% v/v. The analytes were detected at a wavelength of 230 nm at ambient temperature. Furthermore, the proposed liquid chromatographic procedure was validated for linearity, precision, accuracy, stability, and robustness using an experimental design. Analytes were separated with good resolution within 3.5 min. Analytes showed good linearity in a concentration satisfactory to analyze the different ratios of these analytes in the formulations. Pareto charts showed that the flow rate and mobile phase composition have a significant effect on the peak area of analytes and hence need to be carefully controlled, however, the method is robust. Finally, the different formulations consisting of HCZ, AMD, OLM, TEL, and IRB in different ratios were analyzed with high accuracy using an optimized HPLC method and compared with reported methods. Furthermore, the reported HPLC procedure is simple, rapid, and accurate and therefore can used for regular quality control of binary and ternary formulations using the same stationary and mobile phase. [ABSTRACT FROM AUTHOR]

Infectious diseases are illnesses caused by pathogenic microorganisms, including viruses, bacteria, fungi, and parasites. These diseases can be transmitted from one individual to another, as well as through contaminated food, water, and insect bites, infectious agents invade the body, multiply, and disrupt normal bodily functions, leading to various health issues. However, due to antimicrobial resistance, the need to develop nanoenabled medicine gained significant attention recently. The management of infectious diseases using carbon nanotubes (CNTs) is an emerging field that leverages the unique properties of these nanostructures for enhanced drug delivery and therapeutic applications. Therefore, this review explores the transformative potential of CNTs in the diagnosis, prevention, and treatment of infectious diseases. As global health challenges escalate due to emerging pathogens and increasing drug resistance, the need for innovative solutions becomes critical. Moreover, the review systematically examines the unique properties of CNTs, including their mechanical, thermal, and electrical characteristics, that make them suitable for various biomedical applications. Further, the review highlights recent advancements in CNTs-based technologies, focusing on their roles in biosensing, drug deliver, and antiviral agents. Furthermore, the review also discusses how CNTs enhance the sensitivity and specificity of diagnostic tools, enabling rapid detection of infectious agents. Additionally, the multifunctional capabilities of CNTs in therapeutic applications, such as targeted drug delivery and pathogen inactivation, are also discussed. Challenges related to the clinical translation of CNTs technologies, including safety, biocompatibility, and regulatory concerns, are critically analyzed. In addition, the review concludes with clinical data by emphasizing the need for interdisciplinary collaboration to harness the full potential of CNTs in the management of infectious diseases, paving the way for future research and development in this promising field. [ABSTRACT FROM AUTHOR]

Three rapid, accurate, and ecofriendly processed spectrophotometric methods were validated for the concurrent quantification of remogliflozin (RGE) and vildagliptin (VGN) from formulations using water as dilution solvent. The three methods developed were based on the calculation of the peak height of the first derivative absorption spectra at zero-crossing points, the peak amplitude difference at selected wavelengths of the peak and valley of the ratio spectra, and the peak height of the ratio first derivative spectra. All three methods were validated adapting the ICH regulations. Both the analytes showed a worthy linearity in the concentration of 1 to 60 µg/mL and 2 to 90 µg/mL for VGN and RGE, respectively, with an exceptional regression coefficient (r2 ≥ 0.999). The developed methods demonstrated an excellent recovery (98.00% to 102%), a lower percent relative standard deviation, and a relative error (less than ±2%), confirming the specificity, precision, and accuracy of the proposed methods. In addition, validated spectrophotometric methods were commendably employed for the simultaneous determination of VGN and RGE from solutions prepared in the laboratory and the formulation. Hence, these methods can be utilized for the routine quality control study of the pharmaceutical preparations of VGN and RGE in pharmaceutical industries and laboratories. The ecofriendly nature of the anticipated spectrophotometric procedures was confirmed by the evaluation of the greenness profile by a semi-quantitative method and the quantitative and qualitative green analytical procedure index (GAPI) method. [ABSTRACT FROM AUTHOR]