An insilico study of KLK-14 protein and its inhibition with curcumin and its derivativesJyothi Bandi, Vasavi Malkhed, and Navaneetha Nambigari Department of Chemistry, Osmania University, University College of Science, Hyderabad, India
E-mail: mvasavi@osmania.ac.in Received: 9 December 2021 Accepted: 1 April 2022 Abstract: Human kallikrein-related peptidases (KLKs) of serine protease family are known to be expressed in diverse cancers via dysregulated protease activation. KLKs have been associated with pathological angiogenesis of tumor metastasis. KLK-14 expression is highly involved in ovarian, breast, and prostate tumors through explicitly catalyzing the Extracellular matrix protein (fibronectin) hydrolysis. Hence KLK-14 protein is considered the target to study its interaction with curcumin and its derivatives. The present work focuses on creating the 3D model of KLK-14 (Target Protein) by using the homology modeling technique. The 3D model of the target protein is MD Simulated and validated via the Ramachandran plot (90.80% of amino acids in the favorable region) and ProSA-webserver (z-value = − 6.18) indicating the overall reliability of the built model. Further Protein–Protein docking with its natural substrate (Fibronectin) validates the active site residues. Virtual Screening using an In-house library of Curcumin derivatives was performed by AutoDock Vina 4.2 (PyRx software). Curcumin and its derivative (BisDemethoxycurcumin) bind to the target protein (Catalytic triad residues Arg 65, Phe66, Leu67, His83, Arg86, Tyr174, and Ser220) with Binding free energy in the range of − 9.4 to − 7.4 kcal/mol, and also permissible ADME indicating substrate specificity to act as a potential inhibitor of angiogenesis. Graphical abstract Keywords: Angiogenesis; Homology modeling; Active site; Docking; Virtual screening Full paper is available at www.springerlink.com. DOI: 10.1007/s11696-022-02209-w
Chemical Papers 76 (8) 4955–4966 (2022) |
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