ddac093df0fe71fc226d6f892e701676 ijms-25-09446.pdf 922d123d23a4e15d5769bec1e851806a77d319fe ijms-25-09446.pdf 43ce8d01d0df42925290489647a324eca83ac2eb765f20343df13b385fc84865 ijms-25-09446.pdf Title: Applying Molecular Modeling to the Design of Innovative, Non-Symmetrical CXCR4 Inhibitors with Potent Anticancer Activity Subject: The identification of new compounds with potential activity against CXC chemokine receptor type 4 (CXCR4) has been broadly studied, implying several chemical families, particularly AMD3100 derivatives. Molecular modeling has played a pivotal role in the identification of new active compounds. But, has its golden age ended? A virtual library of 450,000 tetraamines of general structure 8 was constructed by using five spacers and 300 diamines, which were obtained from the corresponding commercially available cyclic amines. Diversity selection was performed to guide the virtual screening of the former database and to select the most representative set of compounds. Molecular docking on the CXCR4 crystal structure allowed us to rank the selection and identify those candidate molecules with potential antitumor activity against diffuse large B-cell lymphoma (DLBCL). Among them, compound A{17,18} stood out for being a non-symmetrical structure, synthetically feasible, and with promising activity against DLBCL in in vitro experiments. The focused study of symmetrical-related compounds allowed us to identify potential pre-hits (IC50~20 M), evidencing that molecular design is still relevant in the development of new CXCR4 inhibitor candidates. Keywords: CXCR4; virtual screening; molecular design; DLBCL Author: Miquel Martínez-Asensio, Lluís Sàrrias, Gema Gorjón-de-Pablo, Miranda Fernández-Serrano, Judith Camaló-Vila, Albert Gibert, Raimon Puig de la Bellacasa, Jordi Teixidó, Gaël Roué, José I. Borrell and Roger Estrada-Tejedor Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25 CreationDate: Fri Aug 30 14:06:17 2024 CEST ModDate: Sat Aug 31 03:51:34 2024 CEST Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 14 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 3695611 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- JUXSQN+VnURWPalladioL-Bold Type 1 Custom yes yes yes 10 0 NKXLQD+EURM10 Type 1 Builtin yes yes yes 16 0 BRJHRQ+URWPalladioL-Bold Type 1 Custom yes yes yes 21 0 ODZQQB+URWPalladioL-Roma Type 1 Custom yes yes yes 27 0 DXGVFT+URWPalladioL-Ital Type 1 Custom yes yes yes 32 0 EUNBMT+VnURWPalladioL Type 1 Custom yes yes yes 37 0 IRWHZX+TimesNewRomanPSMT Type 1C WinAnsi yes yes no 53 0 CKUPDE+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 56 0 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SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 600 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Results and Discussion Destination: section.2 Children: Item: Title: Prediction of the Binding Mechanism Destination: subsection.2.1 Item: Title: Synthesis of the Selected Compounds Destination: subsection.2.2 Item: Title: Assessment of the Biological Activity of Selected Candidates Destination: subsection.2.3 Item: Title: Materials and Methods Destination: section.3 Children: Item: Title: Combinatorial Library Enumeration Destination: subsection.3.1 Item: Title: Molecular Docking Destination: subsection.3.2 Item: Title: Molecular Dynamics Simulations Destination: subsection.3.3 Item: Title: General Destination: subsection.3.4 Item: Title: Synthesis Destination: subsection.3.5 Item: Title: Cell Lines and Primary Cultures Destination: subsection.3.6 Item: Title: MTT Proliferation Assay Destination: subsection.3.7 Item: Title: Conclusions Destination: section.4 Item: Title: References Destination: appendix.A. Info: Title: Applying Molecular Modeling to the Design of Innovative, Non-Symmetrical CXCR4 Inhibitors with Potent Anticancer Activity Author: Miquel Martínez-Asensio, Lluís Sàrrias, Gema Gorjón-de-Pablo, Miranda Fernández-Serrano, Judith Camaló-Vila, Albert Gibert, Raimon Puig de la Bellacasa, Jordi Teixidó, Gaël Roué, José I. Borrell and Roger Estrada-Tejedor Subject: The identification of new compounds with potential activity against CXC chemokine receptor type 4 (CXCR4) has been broadly studied, implying several chemical families, particularly AMD3100 derivatives. Molecular modeling has played a pivotal role in the identification of new active compounds. But, has its golden age ended? A virtual library of 450,000 tetraamines of general structure 8 was constructed by using five spacers and 300 diamines, which were obtained from the corresponding commercially available cyclic amines. Diversity selection was performed to guide the virtual screening of the former database and to select the most representative set of compounds. Molecular docking on the CXCR4 crystal structure allowed us to rank the selection and identify those candidate molecules with potential antitumor activity against diffuse large B-cell lymphoma (DLBCL). Among them, compound A{17,18} stood out for being a non-symmetrical structure, synthetically feasible, and with promising activity against DLBCL in in vitro experiments. The focused study of symmetrical-related compounds allowed us to identify potential pre-hits (IC50~20 M), evidencing that molecular design is still relevant in the development of new CXCR4 inhibitor candidates. 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