ABSTRACT
Osteogenesis imperfecta (OI) commonly involving defects in COL1A1 and COL1A2 is a rare hereditary disease of bone fragility affecting 6-7 per 100,000 population. On the other hand, hypopituitarism is a separate entity that manifests with reduced levels of pituitary hormones. The cooccurrence of these two is seldom reported previously in literature as a deviation from Occam's razor. Here, we reported a case of pathological fracture in a 31-year-old male who had blue sclera and secondary adrenal insufficiency, hypogonadotropic hypogonadism, and growth hormone deficiency along with primary autoimmune hypothyroidism. Diagnosis of OI was suggested by heterozygous missense variant in exon 40 of the COL1A2 gene (chr7: g.94423092G > A; Depth: 99×) that resulted in the amino acid substitution of Serine for Glycine at codon 847. Replacement of glucocorticoid, levothyroxine, and testosterone was started along with antiresorptive therapy for better bone health outcomes.
ABSTRACT
BACKGROUND: The abnormal signaling from tyrosine kinase causes many types of cancers, including breast cancer, non-small cell lung cancer, and chronic myeloid leukemia. This research reports the in silico, synthesis, and in vitro study of novel pyrimidine derivatives as EGFR inhibitors. OBJECTIVE: The objective of the research study is to discover more promising lead compounds using the drug discovery process, in which a rational drug design is achieved by molecular docking and virtual pharmacokinetic studies. METHODS: The molecular docking studies were carried out using discovery studio 3.5-version software. The molecules with good docking and binding energy score were synthesized, and their structures were confirmed by FT-IR, NMR, Mass and elemental analysis. Subsequently, molecules were evaluated for their anti-cancer activity using MDA-MB-231, MCF-7, and A431 breast cancer cell lines by MTT and tyrosine kinase assay methodology. RESULTS: Pyrimidine derivatives displayed anti-cancer activity. Particularly, compound R8 showed significant cytotoxicity against MDA-MB-231 with an IC50 value of 18.5±0.6µM. Molecular docking studies proved that the compound R8 has good binding fitting by forming hydrogen bonds with amino acid residues at ATP binding sites of EGFR. CONCLUSION: Eight pyrimidine derivatives were designed, synthesized, and evaluated against breast cancer cell lines. Compound R8 significantly inhibited the growth of MDA-MB-231 and MCF-7. Molecular docking studies revealed that compound R8 has good fitting by forming different Hydrogen bonding interactions with amino acids at the ATP binding site of epidermal growth factor receptor target. Compound R8 was a promising lead molecule that showed better results as compared to other compounds in in vitro studies.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Design , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/metabolism , Humans , Molecular Docking Simulation , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
Vascular complications in forms of venous and arterial thrombi are common scenario in antiphospholipid syndrome with raised titer of antibodies. Here we describe an 18 years old female who was admitted with right parotid swelling due to external carotid artery thrombi within gland parenchyma in antiphospholipid syndrome, with past history of right lower leg arterial occlusion and digital gangrene.