title: Molecular docking and dynamic simulation evaluation of Rohinitib - Cantharidin based novel HSF1 inhibitors for cancer therapy.
abstract: Recent developments in the target based cancer therapies have identified HSF1 as a novel non oncogenic drug target. The present study delineates the design and molecular docking evaluation of Rohinitib (RHT) - Cantharidin (CLA) based novel HSF1 inhibitors for target-based cancer therapy. Here, we exploited the pharmacophoric features of both the parent ligands for the design of novel hybrid HSF1 inhibitors. The RHT-CLA ligands were designed and characterized for ADME/Tox features, interaction with HSF1 DNA binding domain and their pharmacophoric features essential for interaction. From the results, amino acid residues Ala17, Phe61, His63, Asn65, Ser68, Arg71 and Gln72 were found crucial for HSF1 interaction with the Heat shock elements (HSE). The hybrid ligands had better affinity towards the HSF1 DNA binding domain, in comparison to RHT or CLA and interacted with most of the active site residues. Additionally, the HSF1-ligand complex had a reduced affinity towards HSE in comparison to native HSF1. Based on the results, ligand RC15 and RC17 were non carcinogenic, non mutagenic, completely biodegradable under aerobic conditions, had better affinity for HSF1 (1.132 and 1.129 folds increase respectively) and diminished the interaction of HSF1 with HSE (1.203 and 1.239 folds decrease respectively). The simulation analysis also suggested that the ligands formed a stable complex with HSF1, restraining the movement of active site residues. In conclusion, RHT-CLA hybrid ligands can be used as a potential inhibitor of HSF1 for non-oncogene target based cancer therapy.
authors.affiliation: Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal 721302, India. Electronic address: tarun3agarwal5@gmail.com.
authors.forename: Tarun
authors.initials: T
authors.lastname: Agarwal
authors.affiliation: Advanced Medical and Dental Institute, Universiti Sains Malaysia, 13200, Bertam, Pulau Pinang, Malaysia. Electronic address: nithyanny90@hotmail.com.
authors.forename: Nithyanan
authors.initials: N
authors.lastname: Annamalai
authors.affiliation: Advanced Centre for Bioengineering and Bioinformatics (ACBB), Integral Research Centre (IRC), Department of Bioengineering, Integral University, Lucknow, Uttar Pradesh 226026, India. Electronic address: akhursheed12@gmail.com.
authors.forename: Asif
authors.initials: A
authors.lastname: Khursheed
authors.affiliation: Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal 721302, India. Electronic address: tkmaiti@hijli.iitkgp.ernet.in.
authors.forename: Tapas Kumar
authors.initials: TK
authors.lastname: Maiti
authors.affiliation: Advanced Medical and Dental Institute, Universiti Sains Malaysia, 13200, Bertam, Pulau Pinang, Malaysia. Electronic address: hasni@amdi.usm.edu.my.
authors.forename: Hasni Bin
authors.initials: HB
authors.lastname: Arsad
authors.affiliation: Advanced Centre for Bioengineering and Bioinformatics (ACBB), Integral Research Centre (IRC), Department of Bioengineering, Integral University, Lucknow, Uttar Pradesh 226026, India. Electronic address: mohdharis.siddiqui@gmail.com.
authors.forename: Mohammed Haris
authors.initials: MH
authors.lastname: Siddiqui
mesh_terms: D020816:Amino Acid Motifs; D000970:Antineoplastic Agents / Q000737:chemistry*; D001572:Benzofurans / Q000737:chemistry*; D002193:Cantharidin / Q000737:chemistry*; D020134:Catalytic Domain; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015195:Drug Design; D000076249:Heat Shock Transcription Factors; D057166:High-Throughput Screening Assays; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D040681:Structural Homology, Protein; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry; D014584:User-Computer Interface
chemical_list: D000970:Antineoplastic Agents; D001572:Benzofurans; D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D008024:Ligands; D014157:Transcription Factors; D002193:Cantharidin
keywords: Cantharidin; Heat shock factor 1 (HSF1); Molecular dynamic simulation; Non-oncogene target based cancer therapy; Rohinitib