PMID- 34753081 OWN - NLM STAT- MEDLINE DCOM- 20220203 LR - 20220203 IS - 1879-0534 (Electronic) IS - 0010-4825 (Linking) VI - 139 DP - 2021 Dec TI - Combination of docetaxel and newly synthesized 9-Br-trimethoxybenzyl-noscapine improve tubulin binding and enhances antitumor activity in breast cancer cells. PG - 104996 LID - S0010-4825(21)00790-3 [pii] LID - 10.1016/j.compbiomed.2021.104996 [doi] AB - To strategically design and frame the novel 9-Br-Trimethoxybenzyl noscapine (BTN) with rigorous binding affinity with tubulin, the structure of noscapine (an antitussive plant alkaloid) was amended with a 3,4,5-trimethoxybenzyl group linked at the seventh position on the lower isobenzofuran unit. Molecular modelling and cellular studies were used to assess the single and combined effects of BTN and docetaxel (DOX). Based on MM-GBSA, the individual calculated free energies of binding (DeltaG(bind, pred)) for BTN and DOX with tubulin was found to be -25.69 and -38.17 kcal/mol, respectively, and -29.11 and -36.60 kcal/mol based on MM-PBSA. Furthermore, the DeltaG(bind,)(pred) of BTN was dramatically reduced (-30.02 and -33.54 kcal/mol using MM-GBSA and MM-PBSA) in presence of DOX on its binding pocket. Parenthetically, the DeltaG(bind,)(pred) of DOX was substantially decreased (-39.17 and -35.80 kcal/mol using MM-GBSA and MM-PBSA) in the presence of BTN on its binding pocket. The synergistic activity of both compounds on tubulin dimmer was also analysed using purified tubulin, where a combined regimen of BTN and DOX attenuated tubulin intensity to a higher value (50%) particularly in comparison to the single regimen. In comparison to the single regimen, the combination of BTN and DOX effectively prevents cell cycle progression during the G2/M phase and induces breast cancer cell death. Female athymic nude mice were xenografted with MCF-7 cells and the efficacy of (150 mg/kg/day), DOX (1.5 mg/kg/week, i.v.), or in combination (BTN 300 mg/kg/day + DOX 1.0 mg/kg/week, i.v) were evaluated. CI - Copyright (c) 2021. Published by Elsevier Ltd. FAU - Dash, Shruti Gamya AU - Dash SG AD - Centre of Excellence in Natural Products and Therapeutics, Department of Biotechnology and Bioinformatics, Sambalpur University, Jyoti Vihar, Burla, Sambalpur, 768 019, Odisha, India. FAU - Kantevari, Srinivas AU - Kantevari S AD - Fluoro and Agrochemicals Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 007, India. FAU - Guru, Santosh Kumar AU - Guru SK AD - Department of Biological Sciences (Pharmacology & Toxicology), National Institute of Pharmaceutical Education and Research. Hyderabad, Telangana, 500 037, India. FAU - Naik, Pradeep Kumar AU - Naik PK AD - Centre of Excellence in Natural Products and Therapeutics, Department of Biotechnology and Bioinformatics, Sambalpur University, Jyoti Vihar, Burla, Sambalpur, 768 019, Odisha, India. Electronic address: pknaik1973@gmail.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20211029 PL - United States TA - Comput Biol Med JT - Computers in biology and medicine JID - 1250250 RN - 0 (Antineoplastic Agents) RN - 0 (Tubulin) RN - 15H5577CQD (Docetaxel) RN - 8V32U4AOQU (Noscapine) SB - IM MH - Animals MH - *Antineoplastic Agents/pharmacology MH - *Breast Neoplasms/drug therapy MH - Docetaxel/pharmacology MH - Female MH - Humans MH - Mice MH - Mice, Nude MH - Molecular Docking Simulation MH - *Noscapine/pharmacology MH - Tubulin OTO - NOTNLM OT - Anti-tumour activity OT - BTN OT - Combination drug therapy OT - DOX OT - Molecular docking OT - Tubulin binding affinity EDAT- 2021/11/10 06:00 MHDA- 2022/02/04 06:00 CRDT- 2021/11/09 20:21 PHST- 2021/10/02 00:00 [received] PHST- 2021/10/24 00:00 [revised] PHST- 2021/10/25 00:00 [accepted] PHST- 2021/11/10 06:00 [pubmed] PHST- 2022/02/04 06:00 [medline] PHST- 2021/11/09 20:21 [entrez] AID - S0010-4825(21)00790-3 [pii] AID - 10.1016/j.compbiomed.2021.104996 [doi] PST - ppublish SO - Comput Biol Med. 2021 Dec;139:104996. doi: 10.1016/j.compbiomed.2021.104996. Epub 2021 Oct 29.