Fluorinated phospholipid analogs Edelfosine and Ilmofosine drug reveal expressive potential as antineoplastic factors though targeted interaction with heat shock protein (HSP70KDa1A), an essential mediator in cancer pathophysiology. Using evolved computational approaches, this research evaluated their ADMET (absorption, distribution, metabolism, excretion and toxicity) profiles receptor binding affinities and molecular dynamics. Molecular docking discernible vigorous interactions with Edelfosine drug displaying greater binding stability and consistent hydrogen bonding as confirmed by 100 ns molecular dynamics simulations. Comparative interpretation emphasized Edelfosine drug enhanced pharmacokinetic properties depicted by lower RMSD values, stable solvent-accessible surface area and reduced structural fluctuations relative to Ilmofosine drug. Functional annotation and phylogenetic investigation affirmed the evolutionary conservation and pivotal biological function of heat shock protein (HSP70KDa1A). These findings position Edelfosine drug as a promising candidate for targeted cancer therapy appropriated further experimental validation to elucidate its mechanisms of action and therapeutic efficacy.

Postaxial Polydactyly (PAP) is a congenital disorder of limb abnormalities characterized by posterior extra digits. Mutations in the N-terminal region of the Zinc finger protein 141 (ZNF141) gene were recently linked with PAP type A. Zinc finger proteins exhibit similarity at their N-terminal regions due to C2-H2 type Zinc finger domains, but their functional preferences vary significantly by the binding patterns of DNA. Methods: This study delineates the pathogenic association, miss-fold aggregation, and conformational paradigm of a missense variant (c.1420C > T; p.T474I) in ZNF141 gene segregating PAP through a molecular dynamics simulations approach. Results: In ZNF141 protein, helices play a crucial role by attaching three specific target DNA base pairs. In ZNF141^T474I protein, H1, H3, and H6 helices attain more flexibility by acquiring loop conformation. The outward disposition of the proximal portion of H9-helix in mutant protein occurs due to the loss of prior beta-hairpins at the C terminal region of the C2-H2 domain. The loss of hydrogen bonds and exposure of hydrophobic residues to solvent and helices turning to loops cause dysfunction of ZNF141 protein. These significant changes in the stability and conformation of the mutant protein were validated using essential dynamics and cross-correlation maps, which revealed that upon point mutation, the overall motion of the proteins and the correlation between them were completely different, resulting in Postaxial polydactyly type A. Conclusions: This study provides molecular insights into the structural association of ZNF141 protein with PAP type A. Identification of active site residues and legends offers new therapeutic targets for ZNF141 protein. Further, it reiterates the functional importance of the last residue of a protein.

Alzheimer's disease (AD), the primary cause of dementia and lacks potent therapeutic interventions. Natural biosurfactants containing Surfactin and Rhamnolipid, with neuroprotective capability and anti-inflammatory, extend favorable multi-target approaches. This study examined the therapeutic potential of Surfactin and Rhamnolipid against Alzheimer's disease operating network pharmacology and molecular docking to manifest their multi-target pathways. Network pharmacology was devoted to investigate Alzheimer's comparable targets of Rhamnolipid and Surfactin, observed by enrichment and network assay. Molecular docking and molecular dynamics simulations were then conducted to measure drug-target interactions and stability. Network pharmacology recognized 87 overlapping targets of Rhamnolipid and Surfactin with Alzheimer's disease, with hub genes involving CASP3, SRC, CTNNB1, HSP90AA1 and STAT3. GO and KEGG assessment identified enhancement in pathways related to synaptic signaling, immune regulation, kinase activity, and neuroinflammation. Docking explorations illustrated Rhamnolipid exhibited strong binding affinities, distinctly with 1BYQ (-11.1 kcal/mol), 7SEO (-9.1 kcal/mol), and 2SRC (-9.0 kcal/mol) while Surfactin confirmed weaker interactions. Molecular dynamics simulations (MD) affirmed stable complexes, with the Rhamnolipid CASP3 complex revealing the highest conformational stability. These findings indicate that biosurfactants, especially Rhamnolipid, exert neuroprotective effects against Alzheimer's disease through multi-target and multi-pathway functions. Their strong binding to crucial Alzheimer disease related proteins and stable interactions in dynamic simulations highlight their potential therapeutic agents, validating promote experimental validation.

Hypotrichosis is an uncommon type of alopecia (hair loss) characterized by coarse scalp hair caused by the reduced or fully terminated activity of the Lipase-H (LIPH) enzyme. LIPH gene mutations contribute to the development of irregular or non-functional proteins. Because several cellular processes, including cell maturation and proliferation, are inhibited when this enzyme is inactive, the hair follicles become structurally unreliable, undeveloped, and immature. This results in brittle hair, as well as altered hair shaft development and structure. Because of these nsSNPs, the protein’s structure and/or function may be altered. Given the difficulty in discovering functional SNPs in genes associated with disease, it is possible to assess potential functional SNPs before conducting broader population investigations. As a result, in our in silico analysis, we separated potentially hazardous nsSNPs of the LIPH gene from benign representatives using a variety of sequencing and architecture-based bioinformatics approaches. Using seven prediction algorithms, 9 out of a total of 215 nsSNPs were shown to be the most likely to cause harm. In order to distinguish between potentially harmful and benign nsSNPs of the LIPH gene, in our in silico investigation, we employed a range of sequence- and architecture-based bioinformatics techniques. Three nsSNPs (W108R, C246S, and H248N) were chosen as potentially harmful. The present findings will likely be helpful in future large population-based studies, as well as in drug discovery, particularly in the creation of personalized medicine, since this study provides an initial thorough investigation of the functional nsSNPs of LIPH.

Background and Objectives: Lamellar ichthyosis is a rare skin disease characterized by large, dark brown plate-like scales on the entire body surface with minimum or no erythema. This phenotype is frequently associated with a mutation in the TGM1 gene, encoding the enzyme transglutaminase 1 which plays a catalytic role in the formation of the cornified cell envelop. The present study aimed to carry out clinical and genetic characterization of the autosomal recessive lamellar ichthyosis family from Balochistan. Materials and Methods: A consanguineous family with lamellar ichthyosis was enrolled from Balochistan, Pakistan. PCR amplification of all the exons and splice site junctions of the TGM1 gene followed by Sanger sequencing was performed on the genomic DNA. The identified variant was checked by In silico prediction tools to evaluate the effect of the variant on protein. Results: Sanger sequencing identified a homozygous nonsense variant c.131G >A (p.Trp44*) in the TGM1 gene that segregated in the autosomal recessive mode of inheritance in the family. The identified variant results in premature termination of transcribed mRNA and is predicted to cause a truncated or absent translation product transglutaminase-1 (TGase-1) accompanied by loss of catalytic activity, causing a severe clinical phenotype of lamellar ichthyosis in the patients. Conclusions: Here, we report a consanguineous lamellar ichthyosis family with a homozygous nonsense variant in the TGM1 gene. The variant is predicted as pathogenic by different In silico prediction tools.