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Ataxia telangiectasia-mutated (ATM) protein kinase, a key player in cellular integrity regulation, is known for its role in DNA damage response. This study investigates the broader impact of ATM on cellular processes and potential clinical manifestations arising from mutations, aiming to expand our understanding of ATM's diverse functions beyond conventional roles. The research employs a comprehensive set of computational techniques for a thorough analysis of ATM mutations. The mutation data are curated from dbSNP and HuVarBase databases. A meticulous assessment is conducted, considering factors such as deleterious effects, protein stability, oncogenic potential, and biophysical characteristics of the identified mutations. Conservation analysis, utilizing diverse computational tools, provides insights into the evolutionary significance of these mutations. Molecular docking and dynamic simulation analyses are carried out for selected mutations, investigating their interactions with Y2080D, AZD0156, and quercetin inhibitors to gauge potential therapeutic implications. Among the 419 mutations scrutinized, five (V1913C, Y2080D, L2656P, C2770G, and C2930G) are identified as both disease causing and protein destabilizing. The study reveals the oncogenic potential of these mutations, supported by findings from the COSMIC database. Notably, Y2080D is associated with haematopoietic and lymphoid cancers, while C2770G shows a correlation with squamous cell carcinomas. Molecular docking and dynamic simulation analyses highlight strong binding affinities of quercetin for Y2080D and AZD0156 for C2770G, suggesting potential therapeutic options. In summary, this computational analysis provides a comprehensive understanding of ATM mutations, revealing their potential implications in cellular integrity and cancer development. The study underscores the significance of Y2080D and C2770G mutations, offering valuable insights for future precision medicine targeting-specific ATM. Despite informative computational analyses, a significant research gap exists, necessitating essential in vitro and in vivo studies to validate the predicted effects of ATM mutations on protein structure and function. [ABSTRACT FROM AUTHOR]

Ionotropic glycine receptors (GlyRs) are chloride-permeable ligand-gated ion channels expressed in the nervous system. Alterations to glycinergic inhibition and the generation of dysfunctional GlyRs have been linked to chronic pain, a widely prevalent disease. Positive allosteric modulators (PAMs) targeting GlyRs exerted analgesic effects, motivating research on glycinergic PAMs as potential pain therapies. Rationally designed tricyclic sulfonamides are novel glycinergic PAMs with analgesic activity. However, detailed electrophysiological studies on these PAMs are still limited, and the GlyR binding site structural data has not been yet validated by mutational studies. Here, we combined electrophysiology and bioinformatics to systematically study the AM-1488 actions, a prototypical tricyclic sulfonamide, on recombinant GlyRs. We determined that AM-1488 is a potent, non-selective PAM of mammalian GlyR subtypes. In addition, the compound displayed agonistic activity, with partial preference for α1GlyRs. Single channel assays revealed that the compound increased the channel open probability without changing conductance. Mutational analyses on the tricyclic sulfonamide site confirm the molecular determinants contributing to functional activity. Our findings further define the mechanistic framework underlying the GlyR modulation by this PAM class, suggesting that further structure-driven exploration within the tricyclic sulfonamide site may originate novel glycinergic modulators for future development. [ABSTRACT FROM AUTHOR]

We report in this contribution the synthesis and in vitro biological evaluation of a novel class of chiral thiazoloisoindolinone scaffolds as potent inhibitors against human farnesyltransferase (FTase-h). The targeted products, sulfides (4), sulfoxides (5,6), and sulfones (7), containing up to three points of diversification, were obtained in a short-step sequence starting from the available and cost-effective L-cysteine hydrochloride (1), which is the source of N and S atoms and the chiral pool, and α-carbonyl benzoic acids (2), which are isoindolinone precursors. Concisely, the key ester intermediates (1) provide (a) sulfide-amides (4) by solvent-free amidation, (b) sulfoxides (5,6) by selective S-oxidation using NaIO4, and (c) sulfones (7) by oxidation using MMPP. Finally, the obtained N,S-acetal systems have shown promising inhibitory activities on FTase-h in the nanomolar range with excellent half maximal inhibitory concentration (IC50) values up to 4.0 nanomolar (for example, 25.1 nM for sulfide 4bI, 67.3 nM for sulfone 7bG, and more interesting of 4.03 nM for sulfoxide 5bG). [ABSTRACT FROM AUTHOR]

This study aims to design improved inhibitors targeting the thymidylate kinase (TMK) of Mycobacterium tuberculosis (Mtb), the causative agent of infectious disease tuberculosis that is associated with high morbidity and mortality in developing countries. TMK is an essential enzyme for the synthesis of bacterial DNA. We have performed computer-aided molecular design of MtbTMK inhibitors by modification of the reference crystal structures of the lead micromolar inhibitor TKI1 1-(1-((4-(3-Chlorophenoxy)quinolin-2-yl)methyl)piperidin-4-yl)-5-methylpyrimidine-2,4(1H,3H)-dione bound to TMK of Mtb strain H37Rv (PDB entries: 5NRN and 5NR7) using the computational approach MM-PBSA. A QSAR model was prepared for a training set of 31 MtbTMK inhibitors with published inhibitory potencies ( I C 50 e x p ) and showed a significant correlation between the calculated relative Gibbs free energies of the MtbTMK–TKIx complex formation and the observed potencies. This model was able to explain approximately 95% of the variation in the in vitro inhibition data and validated our molecular model of MtbTMK inhibition for the subsequent design of new TKI analogs. Furthermore, we have confirmed the predictive capacity of this complexation QSAR model by generating a 3D QSAR PH4 pharmacophore-based model. A satisfactory correlation was also obtained for the validation PH4 model of MtbTMK inhibition (R2 = 0.84). We have extended the hydrophobic m-chloro-phenoxyquinolin-2-yl group of TKI1 that can occupy the entry into the thymidine binding cleft of MtbTMK by alternative larger hydrophobic groups. Analysis of residue interactions at the enzyme binding site made it possible to select suitable building blocks to be used in the preparation of a virtual combinatorial library of 28,900 analogs of TKI1. Structural information derived from the complexation model and the PH4 pharmacophore guided the in silico screening of the library of analogs and led to the identification of new potential MtbTMK inhibitors that were predicted to be effective in the low nanomolar concentration range. The QSAR complexation model predicted an inhibitory concentration I C 50 p r e of 9.5 nM for the best new virtual inhibitor candidate TKI 13_1, which represents a significant improvement in estimated inhibitory potency compared to TKI1. Finally, the stability of the MtbTMK–inhibitor complexes and the flexibility of the active conformation of the inhibitors were assessed by molecular dynamics for five top-ranking analogs. This computational study resulted in the discovery of new MtbTMK inhibitors with predicted enhanced inhibitory potencies, which also showed favorable predicted pharmacokinetic profiles. [ABSTRACT FROM AUTHOR]

The MDM2‐p53 pathway plays a pivotal role in regulating cell cycle and apoptosis, with its dysfunction contributing to approximately 50% of human malignancies. MDM2, an E3 ubiquitin ligase, targets the tumour suppressor p53 for degradation, thereby promoting uncontrolled cell growth in cancers. Inhibiting the MDM2‐p53 interaction represents a promising therapeutic strategy for reactivating p53's tumour‐suppressive functions. This study explored the potential of ibutamoren (IBU) as a novel inhibitor of MDM2. In silico analyses utilizing molecular modelling revealed that IBU has a low IC50 for MDM2 inhibition and favourably binds to the p53‐binding pocket of MDM2. In vitro experiments demonstrated that IBU treatment reduced the viability of immortalized cancer cell lines with a functional MDM2‐p53 pathway but not in cell lines where this pathway harboured damaging mutations. This trend was further supported by RT‐qPCR analysis, which showed differential expression of two p53 target genes upon IBU treatment in cell lines with wild MDM2‐p53 pathways but not in those harbouring damaging mutations. These findings provide preliminary evidence supporting IBU's anticancer activity, plausibly through the MDM2‐p53 pathway, and suggest that further studies are warranted to explore its mechanism of action and potential development as a lead compound in oncology research. [ABSTRACT FROM AUTHOR]

Skin aging is a natural process of change in all living organisms, it is associated with cell maturation. Cells gradually lose function on exposure to factors such as sunlight, pollution, or prolonged contact with chemicals. Patchouli Essential Oil (PEO) extracted from Patchouli Plant (Pogostemon cablin Benth.) is known to have antioxidants and anti-aging properties. Therefore, this study aimed to determine the potential of PEO as an anti-aging agent using in silico methods. PEO Chemical Profiling was done using Gas Chromatography-Mass Spectrometry (GC-MS). Each PEO active molecule was subjected to ADME (Adsorption, Distribution, Metabolism, and Excretion) analysis using Lipinski's Rule of Five and LogKp (Skin Permeability) in the SwissADME database, followed by toxicity test using the ProTox-II database. Each of the selected compounds was subjected to reverse docking against skin-aging proteins known to play important roles in the aging process including MMP13 (Collagenase), MMP9 (Gelatinase), and hyaluronidase using the Autodock Vina program integrated into the PyRx software. In addition, Molecular Dynamics Simulation (MDS) was carried out using YASARA (Yet Another Scientific Artificial Reality Application) v.23.5.19 software. GC-MS analysis of PEO detected 44 compounds, out of which 26 compounds with anti-aging potential were selected based on ADME and toxicity studies. Molecular docking result showed that the compound 3, 7, 11-trimethyldodeca-2, 4, 6, 10-tetraenal had the lowest binding energy value (-8.2 Kcal/mol) against the MMP9 protein. MDS data also demonstrated excellent interaction between ligand molecule and MMP9 protein. These results imply that PEO compounds may inhibit the function of skin-aging proteins. [ABSTRACT FROM AUTHOR]

The decline in anticancer drugs is a constant problem in both basic and advanced medicine .It suggests using a theoretical chemical study to identify potential drugs using Dioxoisoindoline derivatives. The study utilized molecular docking and ΔG, comes to this conclusion. The chemical and protein more closely match when the negative G value is higher calculations to evaluate the derivatives' activity against cancer-related proteins. Several compounds, including S4, S1, and S1, demonstrated significant activity against different proteins. The ΔG values obtained for all derivatives fell within an acceptable range, indicating their potential as therapeutic agents. These findings suggest that the studied Dioxoisoindoline derivatives possess promising properties for targeting various cancer-related proteins. The text emphasizes the importance of developing alternative anticancer drugs and introduces a chemical study approach using these derivatives. The compounds tested showed promising activity against specific proteins, making them potential candidates for further research and development as potential anticancer medications.

RG1 is a quadruplex‐forming sequence in the SARS‐CoV‐2 genome proposed as possible therapeutic target for COVID‐19. We demonstrate that the dominant conformation of RG1 under physiological conditions differs from the parallel quadruplex previously assumed. Through comprehensive investigations employing CD, UV, NMR, DSC, gel electrophoresis, MD simulations, in silico spectroscopy and the use of truncated RG1 sequences, we have identified this stable conformation as an RNA G‐triplex composed of two G‐triads. We believe this previously unreported RNA structure could serve as a novel therapeutic target. Our findings open new avenues for further studies on the presence and biological role of RNA G‐triplexes in vivo. [ABSTRACT FROM AUTHOR]

Class IIa histone deacetylases (HDACs) have been linked to tumorigenesis in various cancers. Previously, we designed phenylhydroxamic acid LH4f as a potent class IIa HDAC inhibitor. However, it also unselectively inhibited class I and class IIb HDACs. To enhance the compound's selectivity towards class IIa HDACs, the ortho-phenyl group from the selective HDAC7 inhibitor 1 is incorporated into ortho position of the phenylhydroxamic acid in LH4f. Compared to LH4f, most resulting compounds displayed substantially improved selectivity towards the class IIa HDACs. Notably, compound 7 g exhibited the strongest HDAC9 inhibition with an IC50 value of 40 nM. Molecular modelling further identified the key interactions of compound 7 g bound to HDAC9. Compound 7 g significantly inhibited several human cancer cells, induced apoptosis, modulated caspase-related proteins as well as p38, and caused DNA damage. These findings suggest the potential of class IIa HDAC inhibitors as lead compounds for the development of cancer therapeutics. [ABSTRACT FROM AUTHOR]

In this study, we employ spectroscopic, thermodynamic and molecular docking approaches to identify the mechanism by which thiazolidinone derivatives 4a–4d bind with human serum albumin. It has been suggested that the affinity of the interaction of derivatives 4a–4d with HSA is within the optimal range necessary for the transportation and distribution of compounds within the organism. The binding constant values for the derivative/HSA complexes were found to be 0.03–5.87 × 105 M−1. Both ΔH0 and ΔS0 values were negative, which indicates that binding occurs mainly through van der Waals forces and hydrogen bonding. The negative values calculated for ΔG0 indicate that the binding of derivatives 4a–4d with HSA is a spontaneous process. Our study also reveals that derivatives 4a–4d bind to the subdomain IB (Site III) of HSA and that this binding alters the conformation and thermodynamic stability of HSA. Molecular docking simulations suggest that the main binding forces are van der Waals interactions, hydrophobic interactions and hydrogen bonds. The studied compounds showed weak DPPH‐scavenging activity at all of the tested concentrations. The results suggest that compound 4b with a phenyl substituent at the nitrogen atom of the 1,3‐thiazolidin‐4‐one moiety can be considered the most potent antioxidant in the series. [ABSTRACT FROM AUTHOR]

Xanthine dehydrogenase (XDH) contributes significantly to generating reactive oxygen species in coronary artery disease (CAD). XDH has been proposed as a therapeutic target, but its genetic variants could affect protein structure and drug response. We aimed to assess protein structure modification occur due to genetic variants and to screen 215 CAD drugs for their utility in personalized CAD treatment against the XDH variants. A series of computational methods were implemented to identify pathogenic variants that cause XDH structure instability localized at the con served regions contributing to functional significance. Then, the XDH structures with the pathogenic variants were modeled using two different approaches to select the best models for docking with the CAD drugs. Finally, the stability of the docked complexes and their ability to transfer electrons were evaluated using molecular dynamics (MD) simulations and quantum mechanics/molecular mechanics (QM/MM) calculation. Among 751 variants examined; R149C and Q919R showed high pathogenicity, localized in conserved regions could alter protein structure and function. Further, docking of CAD drugs against XDH (native, R149C and Q919R) showed vericiguat with higher affinity, ranging from −7.95 kcal/mol to −10.41 kcal/mol, than the well-known XDH inhibitor (febuxostat, −5.73 kcal/mol to −8.35 kcal/mol). This indicates that vericiguat will be effective in CAD treatment, regardless of the XDH variants. Additionally, MD simulation and QM/MM confirmed vericiguat stability and electron transfer ability to form hydrogen bonds with the XDH protein. In conclusion, vericiguat will be beneficial for the personalized treatment of CAD by inhibiting XDH variants. Additional clinical studies are necessary to confirm our findings. This study identified two highly pathogenic XDH variants, R149C and Q919R, emphasizing the genetic variability that influences drug response in CAD. Molecular docking studies revealed that vericiguat may be a better inhibitor for XDH native and variant structures, exhibiting stronger binding affinities than febuxostat. QM/MM and MD simulations confirmed that vericiguat has a stable and effective interaction with XDH native and its variants, suggesting its potential as a personalized treatment for CAD. [ABSTRACT FROM AUTHOR]