Тезисы MOLECULAR DOCKING STUDY OF FASCAPLYSIN DERIVATIVES INTERACTION WITH CDK4


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Fascaplysin (Figure 1) is a red pigment that was isolated in 1988 from marine sponge Fascaplysinopsis sp. This alkaloid exhibits antifungal, antibacterial, antiviral properties and anticancer activity against a wide range of tumor cells. Fascaplysin is a highly selective inhibitor of cyclin-dependent kinase 4 (CDK4) which plays a key role in cell cycle regulation and is an important target for anticancer drugs [1].

fascaplysin,cdk4, фаскаплизин
1

Figure 1. Molecular structure of fascapysin 1

In this research docking study of several fascaplysin derivatives was performed against CDK4 in order to reveal the most perspective compounds for further synthesis and exploration.
However, in spite of antitumor activity, fascaplysin itself can’t be used for cancer treatment because of high toxicity explained by DNA intercalationability of fascaplysin. It was supposed that insertion of flexible groups into framework would prevent interaction with DNA. Available synthetic techniques allow us to pursue structure modifications in position 9. We expect that introduction of substituent in position 9 of basic structure would improve the binding affinity to cyclin-dependent kinase 4.
The docking procedure was executed with Autodock4 software according to user manual [2].We exploredthe interaction of 135 fascaplysin derivatives with various substituents in position 9 (Table 1) with the active site of CDK4 homology model [3]. The skeleton was modified by both cyclic and acyclic substituents.

Table 1. Fascaplysin derivatives

fascaplysin,cdk4, фаскаплизин
R1=
NO2, Halogen, OH, N, Ph;
CH2OH, COOH, COOEt, C(O)Me, C(O)Et, C(O)NH2;
OC(O)CH2(Me)Et, OC(O)CH2i-Pr,
OC(O)CH2CH(NH2)COOH, OC(O)(CH2)2CH(NH2)COOH;
NH(CH2)nCOOH; n=1-3.
fascaplysin,cdk4, фаскаплизин
R1=
Bu, (CH2)nt-Bu, CH(Me)CH2(Me), CH(Me)i-Pr,
(CH2)2CH(NH2)COOH
(CH2)nMe; n=1-3;
Naphthyl, BzNHBz.
fascaplysin,cdk4, фаскаплизин
X=N;
R1, R2=NO2, Halogen, Me, OH, N+ — substituent position 1-4.
fascaplysin,cdk4, фаскаплизин
R1,R2=
NO2, Halogen, Me, Et, OH;
OMe, OEt, NHMe, NHEt, CH2NHMe, C(O)Me;, NHC(O)Me — substituent position 1-4;
R3= Me, Et, Ph.
fascaplysin,cdk4, фаскаплизин
fascaplysin,cdk4, фаскаплизин R1,R2=NO2, Halogen, Me, OH — substituent position 1-4.
fascaplysin,cdk4, фаскаплизин
fascaplysin,cdk4, фаскаплизин
fascaplysin,cdk4, фаскаплизин
fascaplysin,cdk4, фаскаплизин

The binding energies of most derivatives in absolute value exceeded the same parameter for fascaplysin showing a promising outlook of studied compounds. The best derivative in terms of energy value (-11,2 kkal/mol) is compound 2 (Figure 2).

fascaplysin,cdk4, фаскаплизин
2

Figure 2. Molecular structure of best energy value compound 2

An array of derivatives bound to receptor according to fascaplysin preserving the unique pattern of molecular contacts that define high selectivity to CDK type 4 (Figure 3).

fascaplysin,cdk4, фаскаплизин

Figure 3. Superposition of fascaplysin (light grey) and compound 2 (dark gray) in the active site of CDK4

In several cases derivatives either shifted from the binding pocketbecause of their large size or changed orientation due to realized interactions different from fascaplysin.
Considering both the binding energy score and ligand position in the active site, we have chosen three compounds (Figure 4) for further synthesis and comprehensive research.

fascaplysin,cdk4, фаскаплизин

Figure 4. Molecular structures of chosen compounds 2, 3, 4

The molecular modeling study in this research refers to fascaplysin as highly selective inhibitor of CDK4. To sum up, we established structural components that increase the binding affinity of fascaplysin derivatives to CDK4. In addition, these structural fragments will possibly prevent DNA intercalation what makes fascaplysin derivatives perspective for anticancer drug development. Three fascaplysin derivatives were chosen for synthesis and subsequent detail research.

References:

  1. B. Bharate, S., Manda, S., Mupparapu, N., Battini, N., & A. Vishwakarma, R. (2012). Chemistry and Biology of Fascaplysin, a Potent Marine-Derived CDK-4 Inhibitor. MRMC, 12(7), 650-664. http://dx.doi.org/10.2174/138955712800626719
  2. Morris, G., Huey, R., Lindstrom, W., Sanner, M., Belew, R., Goodsell, D., & Olson, A. (2009). AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem., 30(16), 2785-2791. http://dx.doi.org/10.1002/jcc.21256
  3. Shafiq, M., Steinbrecher, T., &Schmid, R. (2012). FASCAPLYSIN as a Specific Inhibitor for CDK4: Insights from Molecular Modelling. Plos ONE, 7(8), e42612.http://dx.doi.org/10.1371/journal.pone.0042612

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