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0INTERNATIONAL SCIENTIFIC AND PRACTICAL CONFERENCE "STATUS AND DEVELOPMENT PROSPECTS OF FUNDAMENTAL AND APPLIED MICROBIOLOGY: THE VIEWPOINT OF YOUNG SCIENTISTS" _25-26 SEPTEMBER, 2024_
IN SILICO EVALUATION OF CYANOBACTERIAL UV-PROTECTIVE COMPOUNDS EFFICACY TARGETTING HEAT
SHOCK PROTEIN (HSP90)
1Iffat Zareen Ahmad, 2Nida Fatima, 3Sonam Dwivedi
1Professor, Integral University, Lucknow, UP, India, 2Assistant Professor, Integral University, Lucknow, UP, India, 3Student, Integral University, Lucknow, UP, India https://doi.org/10.5281/zenodo.13828922
Abstract. Gram-negative photoautotrophicprokaryotes, cyanobacteria are found all over the earth. They are one of the finest places to get bioactive secondary metabolites. Heat shock proteins have been linked to cell proliferation, differentiation, death, and immune response recognition and have been found to be overexpressed in a variety of human malignancies. In this paper, we have focused on bioactive metabolites reported in cyanobacteria and the involvement of heat shock protein in preventing from UV protection through an in silico approach.
Keywords: UV radiation, cyanobacteria, heat shock protein, bioactive compounds.
INTRODUCTION
We are in the era where we replace synthetic chemicals with the natural products. Cyanobacteria have the potential to produce UV-protective compounds which can be used to develop formulations to be used against damaging effect of UV radiation and intense sunlight. These natural cyanobacterial photoprotectants could be good candidates against synthetic UV filters [1]. Moreover, it has been reported that ketocarotenoid- astaxanthin has vital role in preventing pathological damages in human like photooxidation and skin aging problems [2, 3]. With the recent advances in the field of bioinformatics and in silico analytical tools, the present study was carried out for the in silico screening of UV protective compounds (pharmacophore-based virtual screening) for effective binding with epidermal growth factor receptor in providing protection against the UV radiation.
Hsp90 is a highly conserved protein and comprises about 2% of the total number of expressed cell proteins [4]. Molecular chaperone Hsp90 is required for the stability and maturation of client proteins, essential for cell transformation, proliferation, and survival [5]. Mammalian cells contain three types of Hsp90s: cytosolic Hsp90, mitochondrial Trap-1, and glucose-regulated protein 94 (Grp94) of the endoplasmic reticulum. Each of the Hsp90s including the bacterial homolog HtpG hydrolyzes ATP and undergoes similar conformational changes. Tumor cell oncogenic proteins require Hsp90 for their activity. Thus, Hsp90 appears to be a potential molecular target for cancer prevention and treatment [6]. Consequently, several Hsp90 inhibitors are being evaluated for treatment of various human cancers [6]. However, Hsp90 inhibitors have never been investigated for prevention and treatment of cutaneous SCC.
MATERIALS AND METHODS
Preparation of ligand and protein structure
The 3-dimensional structure of HSP90 were retrieved from Protein Data Bank (PDB ID: 3OWD) (www.rcsb.org) which was used for the docking study (Fig. 1). Energy minimization and force field CHARMm was applied [7] to remove the bad steric clashes. In this implementation, all computations were carried out in without reaction field.
INTERNATIONAL SCIENTIFIC AND PRACTICAL CONFERENCE "STATUS AND DEVELOPMENT PROSPECTS OF FUNDAMENTAL AND APPLIED MICROBIOLOGY: THE VIEWPOINT OF YOUNG SCIENTISTS" _25-26 SEPTEMBER, 2024_
Preparation of ligand structure
The structure of the screened compounds was obtained from the PubChem database. The 3D structures were built using the online server of CORINA (http://www.molecular-networks.com/ products/corina) which were used for the energy minimization of the ligands molecule (Fig. 2). Ligands atoms were added with Gasteiger partial charges.
Fig 1: 3D structure of Heat shock protein (HSP90).
Fucosterol Sargachromenol
\ NJ^H H \ 0 u~
H ^ I Ty pi H o^y^J H0 J]—* Tjtj^H
Pubchem Id:5281328 Pubchemld: 10455044
Fig 2: The chemical structures of fucosterol and sargachromenol which act as ligands.
RESULTS AND DISCUSSION
Docking simulations of fucosterol, sagrachemenol and scytonemin and standard drug EHMC with HSP-90
For understanding the structural basis of protein-ligand interactions docking study was used. Docking studies were conducted on fucosterol and sargachromenol with the standard drug EHMC against HSP-90 target as shown in Fig 3. The compounds were ranked on the basis of binding energy and inhibition constant is given in Table 1. Fucosterol showed highest binding energy of -9.15 -kcal/mol and inhibition constant 197.04p,M as compared to EHMC with the binding energy of -6.24 kcal/mol and inhibition constant 26.58p,M with HSP90. The binding result revealed that the fucosterol showed highest binding energy while sagrachromenol has also favorable binding interaction and inhibition constant, indicating a strong inhibitory activity on the
INTERNATIONAL SCIENTIFIC AND PRACTICAL CONFERENCE "STATUS AND DEVELOPMENT PROSPECTS OF FUNDAMENTAL AND APPLIED MICROBIOLOGY: THE VIEWPOINT OF YOUNG SCIENTISTS" 25-26 SEPTEMBER, 2024
catalytic site of HSP90 than EHMC. These findings suggested that all these showed more affinity with active binding site as compared to standard UV filter EHMC. In addition, it i s already reported that it is also used as a sunscreen in cosmetics [8, 9].
Table 1: Details of AutoDock score, active site pocket residues revealed through molecular docking of fucosterol and sargachromenol with standard drug EHMC, on target Heat shock protein (HSP90).
S. No. Target name Compound Name Binding energy kcal/mol Inhibition constant Residues involved in H bond H bond
1. HSP90 EHMC -6.24 26.58 ASN51, LYS112 2
2. Sargachromenol -8.76 380.67 LYS112,LEU48 ASN106 4
3. Fucosterol -9.15 197.04 0
a)
b)
» HET98
VAL15D /= /VALIΠr : J
ILE110 ASN106 IJNffl 1
; GLV13S
c)
INTERNATIONAL SCIENTIFIC AND PRACTICAL CONFERENCE "STATUS AND DEVELOPMENT PROSPECTS OF FUNDAMENTAL AND APPLIED MICROBIOLOGY: THE VIEWPOINT OF YOUNG SCIENTISTS" _25-26 SEPTEMBER, 2024_
Fig 3: Docked complex of (a) EHMC-HSP90 (b) EHMC-Sagrachromenol (c) EHMC-Fucosterol
CONCLUSION
Photoprotection is a maj or biological concern with respect to the source of natural bioactive molecules that have the anti-photoaging effect and especially, the safer natural sources have been identified in past few decades. Hence, the UV protective compounds from the cyanobacteria have been utilized for further investigational confirmation. The computational approach, molecular docking and average hydrogen bonding affirm that the stability of fucosterol and sargachromenol with HSP90 complexes. However, computational approach suggested that fucosterol may play an effective pharmacological role as compared to conventional drug. Hence, in conclusion it could be said that the ligands bound and interacted well with the proteins HSP90 as compared to the ligand standard drug (EHMC).
REFERENCES
1. Miyata, Y., Nakamoto, H. and Neckers, L., 2013. The therapeutic target Hsp90 and cancer hallmarks. Current Pharmaceutical Design, 19(3), pp.347-365.
2. Guerin, M., Huntley,M.E. and Olaizola, M., 2003. Haematococcus astaxanthin: applications for human health and nutrition. TRENDS in Biotechnology, 21(5), 210-216.
3. Cardozo, K.H., Guaratini, T., Barros, M.P., Falcao, V.R., Tonon, A.P., Lopes, N.P., Campos, S., Torres, M.A., Souza, A.O., Colepicolo, P. and Pinto, E., 2007.Metabolites from algae with economical impact. Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology, 146(1-2), 60-78.
4. Whitesell, L., Santagata, S. and Lin, N.U., 2012. Inhibiting HSP90 to treat cancer: a strategy in evolution. Current Molecular Medicine, 12(9), pp.1108-1124.
5. Mourelle, M., Gómez, C. and Legido, J., 2017. The potential use of marine microalgae and cyanobacteria in cosmetics and thalassotherapy. Cosmetics, 4(4), 46.
6. Biamonte, M.A., Van de Water, R., Arndt, J.W., Scannevin, R.H., Perret, D. and Lee, W.C., 2010. Heat shock protein 90: inhibitors in clinical trials. Journal of Medicinal Chemistry, 53(1), pp.3-17.
7. Alam, S. and Khan, F., 2014. QSAR and docking studies on xanthone derivatives for anticancer activity targeting DNA topoisomerase IIa. Drug Design, Development and Therapy, 8, 183.
8. Rastogi, R.P., Sinha, R.P., Singh, S.P. and Hader, D.P., 2010. Photoprotective compounds from marine organisms. Journal of Industrial Microbiology & Biotechnology, 37(6), 537-558.
9. Rastogi, R.P., Sonani, R.R. and Madamwar, D., 2015. Cyanobacterial sunscreen scytonemin: role in photoprotection and biomedical research. Applied Biochemistry and Biotechnology, 176(6), 1551-1563.
