Abstract
Octamer-binding transcription factor 4 (Oct4) is a core regulator in the retention of stemness, invasive, and self-renewal properties in glioma initiating cells (GSCs) and its overexpression inhibits the differentiation of glioma cells promoting tumor cell proliferation. The Pit-Oct-Unc (POU) domain comprising POU-specific domain (POUS) and POU-type homeodomain (POUHD) subdomains is the most critical part of the Oct4 for the generation of induced pluripotent stem cells from somatic cells that lead to tumor initiation, invasion, posttreatment relapse, and therapeutic resistance. Therefore, the present investigation hunts for natural product inhibitors (NPIs) against the POUHD domain of Oct4 by employing receptor-based virtual screening (RBVS) followed by binding free energy calculation and molecular dynamics simulation (MDS). RBVS provided 13 compounds with acceptable ranges of pharmacokinetic properties and good docking scores having key interactions with the POUHD domain. More Specifically, conformational and interaction stability analysis of 13 compounds through MDS unveiled two compounds ZINC02145000 and ZINC32124203 which stabilized the backbone of protein even in the presence of linker and POUS domain. Additionally, ZINC02145000 and ZINC32124203 exhibited stable and strong interactions with key residues W277, R242, and R234 of the POUHD domain even in dynamic conditions. Interestingly, ZINC02145000 and ZINC32124203 established communication not only with the POUHD domain but also with the POUS domain indicating their incredible potency toward thwarting the function of Oct4. ZINC02145000 and ZINC32124203 also reduced the flexibility and escalated the correlations between the amino acid residues of Oct4 evidenced by PCA and DCCM analysis. Finally, our examination proposed two NPIs that can impede the Oct4 function and may help to improve overall survival, diminish tumor relapse, and achieve a cure not only in deadly disease GBM but also in other cancers with minimal side effects.
Highlights
Glioblastoma Multiforme (GBM) is a common and devastating malignant form of high-grade glioma accounting 70% of central nervous system tumors [1, 2]
Since we hunt to identify small molecule inhibitors to abolish the activity of Octamer-binding transcription factor 4 (Oct4) thereby we focused on the Oct4 POU domain subdivided into POUs and POU-type homeodomain (POUHD) domains [80] which is the most critical part of the protein for induced pluripotent stem cell (iPSC) generation [12, 14]
Oct4, a master regulator of stem cell maintenance can induce pluripotency in somatic cells which cannot be substituted by any paralogous family member
Summary
Glioblastoma Multiforme (GBM) is a common and devastating malignant form of high-grade glioma accounting 70% of central nervous system tumors [1, 2]. Despite surgical resection in combination with radiation therapy and adjunct temozolomide (TMZ) chemotherapy, the clinical prognosis and median overall survival of GBM patients remain grim with 12–14 months and 5-year survival with3-5% after initial diagnosis [3]. Despite its relatively low frequency, GBM is responsible for 4% of all deaths caused by cancer [4]. Recurrence of malignant tumors and therapeutic resistance within months following adjuvant therapy are the key contributors to GBM patient’s death and the major challenges in treatment [5].
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