title: Design and virtual screening towards synthesis of novel substituted thiosemicarbozones as ribonuleotide reductase (RNR) inhibitors with improved cellular trafficking and anticancer activity.
abstract: Ribonucleotide reductase subunit R2 regulates catalytic action of the enzyme to provide DNA synthesis material via reduction. It has been continuously investigated as anticancer drug target for design and discovery of its inhibitors. Present studies aim to design novel heterocyclic/aryl substituted and adamantyl added thiosemicarbazones out fitted with improved cell permeability and effective RNR inhibition. Design strategy renders significant use of virtual screening and molecular docking studies to converge search of selective molecules for synthesis and further experimental studies. Selected candidates were synthesized and evaluated in vitro for their RNR inhibitory activity (IC₅₀, uM) on MCF-7 cells, breast cancer cell lines. Molecular docking results (docking scores) and experimental results (IC₅₀, uM) were found to be correlated and in agreement. Structure-based and ligandbased studies of results substantiate regulative role of water molecules at catalytic site (H₂O: 2057) as well as at RNR inhibitor binding site (H₂O: 2023, 2047, 2060 and 2070). Admantyl group has testified constant spatial position in docked poses and involved in steric interactions with Cys271, Asp272, Phe237, Gly234 and Val238. Heterocyclic/aryl substitutions equally offered H-bonds with water molecules (H₂O: 2028, 2054, 2061 and 2073) along with amino acids Ser264, Asp272, Tyr324 and Asn346. Present efforts to design new inhibitors incur new characteristics in RNR Inhibition.
authors.forename: Niharika
authors.initials: N
authors.lastname: Gokhale
authors.forename: Sanjay
authors.initials: S
authors.lastname: Jain
authors.affiliation: Department of Pharmaceutical Chemistry, Suresh Gyan Vihar University, Jaipur, India-302004. niharikasubhedar@gmail.com.
authors.forename: Mukesh
authors.initials: M
authors.lastname: Yadav
mesh_terms: D020816:Amino Acid Motifs; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001692:Biological Transport; D020134:Catalytic Domain; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D057166:High-Throughput Screening Assays; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D061986:MCF-7 Cells; D062105:Molecular Docking Simulation; D011485:Protein Binding; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013882:Thiosemicarbazones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014584:User-Computer Interface
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D013882:Thiosemicarbazones; D012264:Ribonucleotide Reductases; C108427:ribonucleotide reductase R2 subunit