Journal of molecular graphics & modelling最新文献

Nocardiosis, an infectious disease most commonly caused by the nosocomial pathogen Nocardia asteroides, predominantly affects immunosuppressed individuals and often presents as a pulmonary infection transmitted through inhalation. Although initial drugs like sulfadiazine and sulfisoxazole were used, their poor tissue penetration and the requirement for prolonged therapy have led to their exclusion from current treatment regimens. Consequently, there is a growing demand for novel therapeutics to suppress the pathogenic activity of N. asteroides. The pathogenic strain NCTC11293 of N. asteroides demonstrated a high completeness level of 98.19% in the CheckM analysis, with PGAP annotation identifying 6485 proteins. Given its clinical relevance and resistance profile, the NOCAP analysis revealed glycosyltransferase as a potential drug target associated with drug resistance and pathogenicity. The predicted and validated structure of the glycosyltransferase protein (accession WP_019050588.1) was subjected to structure-based virtual screening using the Schrödinger Suite against marine and phytochemical databases, including CMNPD, SWMD and IMPPAT. This multi-tier screening identified four promising hit molecules: CMNPD1518, CMNPD23345, SWMDGA001, and IMPY466077. The docking scores and MM-GBSA binding energies ranged from -7.20 to -8.90 kcal/mol and -49.81 to -59.90 kcal/mol, respectively. These hit molecules adhered to Lipinski's Rule of Five and exhibited accepted pharmacokinetic properties, along with balanced electronic structural characteristics, illustrating their higher reactivity and stability. Molecular dynamics (MD), essential dynamics (ED) analyses, including PCA-based FEL, and DSSP assessments reinforced the structural stability of the glycosyltransferase-phytochemical complexes. These computational findings suggest that the identified molecules represent promising therapeutic candidates for the treatment of nocardiosis.

Molecular dynamics (MD) simulations have carried out to investigate the solvation scenario of ions (Na⁺, K⁺, Cl^-, I^-, NH₄⁺, CH₃COO^-) in the binary water-taurine and ternary water-taurine-urea mixtures at 308 K. The hydrogen bond (H-bond) properties and dynamics of water‒water, taurine‒water, and ammonium/acetate ion‒water are also explored. Our study revealed that monovalent cations have a higher tendency towards oxygen of taurine than water. NH₄⁺ preferably interacts with the oxygen of the sulfonate group, whereas acetate ions are attributed towards the amino-hydrogens of taurine compared to the oxygen and hydrogens of water. It is found that taurine forms stronger H-bonds with water molecules through its amino group indicating the higher donating tendency of taurine. The translational and orientational relaxation dynamics of water molecules are slowed down in both the binary and ternary mixtures. The average lifetime of the water's H-bonds is higher in the ternary mixtures than the binary mixtures. Addition of urea enhances the overall lifetime of the ammonium ion-water (H_AMM…O_WAT) and acetate ion-water (O_ACE…H_WAT) H-bonds. We have also observed that taurine counteracts the denaturation effect of urea on human islet amyloid polypeptide (hIAPP), as evidenced by the secondary structure. The α-helix content of hIAPP is restored with the addition of 0.45 M taurine in 5.60 M urea concentrations.

Spiropyran (SP) derivatives, as stimuli-responsive fluorescent materials, undergo reversible isomerization between closed-ring (SP) and open-ring (merocyanine, MC) forms upon light irradiation, holding promise for applications in optical switches and sensing. However, their excited-state dynamics and the roles of substituents/solvents in photoinduced ring-opening remain elusive. Herein, we use TD-CAM-B3LYP/6-31G(d) to clarify the photoinduced ring-opening mechanism of carboxyl-functionalized SP derivatives (SP-R, R = NO₂, H, OCH₃). Ground-state (S₀) SP-R is stable with high C2-O1 cleavage barriers (15.5-31.4 kcal/mol), impeding spontaneous ring-opening; the electron-withdrawing NO₂ reduces barriers, while the electron-donating OCH₃ increases them. In the excited state (S₁), these barriers are drastically lowered or even eliminated, facilitating SP→MC conversion, with "bright states" identified as S₂ for SP-NO₂ and S₁ for SP-H/SP-OCH₃. Structural changes promote ring-opening, with SP-OCH₃ exhibiting the most pronounced effects. AIM analysis reveals weakened C2-O1 bond covalency in S₁, particularly for SP-H and SP-OCH₃. Solvent polarity modulates stability, dipole moments, and emission properties: polar solvents enhance trans-MC stability, and Trans-MC-OCH₃ emits the longest wavelengths (602.2-639.3 nm) due to extended π-conjugation. This study clarifies SP→MC mechanisms, highlights the regulatory roles of substituents and solvents, and provides guidance for designing photoresponsive materials.

EGFR is a validated drug target in anticancer drug discovery. However, the existing issues of drug resistance, toxicities, and evolving mutations in EGFR have led to the global decline in the putative and potent anti-EGFR therapeutics. To address this gap, drug repurposing or repositioning is a valid technique for drug identification in a quick time and in an economical way. We herein employed the drug repurposing techniques from the library of 3500 approved USFDA small molecules. The initial HTVS (high-throughput virtual screening), followed by XP analysis and molecular mechanics (MMGBSA) and ADME profiling, led to the identification of Cycloguanil (antimalarial) and Metformin (antidiabetic) as the putative lead molecules with the potential to inhibit the EGFR. The top-scoring ligand was subjected to a molecular dynamics simulation study that stabilized the stability of cycloguanil within the ATP pocket of EGFR. The biological investigations further corroborated the in-silico studies. Cycloguanil inhibited the EGFR with a half maximal inhibitory concentration (IC50) of IC₅₀ of 490 nM compared to erlotinib with an IC₅₀ of 222 nM. Besides this, cycloguanil was able to halt the cell cycle progression at the G1 phase (46.54%), a peculiar feature of the kinase inhibitors that affect the CDKs and cyclins required for the passage of cancer cells through G1. Annexin V assay revealed that cycloguanil induced profound apoptosis in A549 cells. The lead molecules were also found to possess cytotoxicity profiles in MCF-7, A549, and HCT-116, which were reported to harbor the expression of EGFR. From the analysis, it was deduced that cycloguanil exhibited the most potent cytotoxicity towards the A549 cell with an IC50 of 6.83 μM, followed by HCT-116 with an IC50 of 9.32 μM, while in MCF-7, it exhibited an IC₅₀ of 14.82 μM. The lead molecule, cycloguanil, may plausibly serve as an important template that may be optimized by performing bioisosteric replacements, leading to a putative kinase inhibitor with a potent anticancer profile.

Tinospora crispa, a plant with widespread use in ethnomedicine, has several extracts as well as phytoconstituents that have been reported to possess anticancer properties. Clerodane-type furano-diterpenoids from this genus of plants show promise as anticancer agents, although only a few of these have been assayed in vitro. 38 clerodane-type furano-diterpenoids from T. crispa were assayed computationally against 13 common anticancer macromolecular targets. The assayed ligand library displayed higher binding affinities than the respective controls in six of the thirteen anticancer macromolecular targets. Binding affinity values that were higher than the respective controls were obtained for two ligands against BRCA1, for four against CDK9/Cyclin T1, for two against C-ROS1, for thirty-seven against EGFR, for three against MEK 1-kinase, and for one against STAT3. Many of these ligands displayed greater binding affinity values than the respective controls against multiple macromolecules. Notable among these are tinocrispide (against BRCA1, C-ROS1, EGFR and MEK1), tinosporol C (against CDK9/Cyclin T1 and MEK1-kinase), crispene E (against BRCA1 and CDK9/Cyclin T1) and (5R,6R,8S,9R,10R,12S)-15,16-Epoxy-2-oxo-6-O-(β-D-glucopyranosyl)-cleroda-3,13(16),14-trien-17,12-olid-18-oic acid methyl ester (against BRCA1 and EGFR). The top scoring compounds of each macromolecule were subjected to molecular dynamics simulations, and the obtained protein-ligand complexes were observed to be stable for all macromolecules except EGFR. The ligand library was mostly predicted to be soluble, but GI absorption was predicted to vary. A few were predicted to be carcinogenic, immunotoxic, and/or cytotoxic. Overall, the clerodane-type furano-diterpenoids from T. crispa show encouraging results in in-silico studies and may be considered for further modification and lead development.