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Newly designed compounds from scaffolds of known actives as inhibitors of survivin: computational analysis from the perspective of fragment-based drug design

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Abstract

Survivin is an apoptosis suppressing protein linked to different forms of cancer. As it stands, there are no approved drugs for the inhibition of survivin in cancer cells despite a number of promising compounds in clinical trials. This study designed a new set of compounds from fragments of active survivin inhibitors to potentiate their binding with survivin at BIR domain. Three hundred and five (305) fragments made from eight potent inhibitors of survivin were reconstructed to form a new set of compounds. The compounds were optimized using R group enumeration and bioisostere replacement after extensive docking analysis. The optimised compounds were filtered by a validated pharmacophore model to reveal how well they are aligned to the pharmacophore sites. Molecular docking of the well aligned compounds revealed the top-scoring compounds; and these compounds were compared with the eight inhibitors used as template for fragment-based design on the basis of binding affinity (rigid and flexible docking), predicted pIC50 and intermolecular interactions. The electronic behaviours (global descriptors, HOMO/LUMO, molecular electrostatic potential and Fukui functions) of newly designed compounds were calculated to investigate their reactivity and atomic sites prone to neutrophilic/electrophilic attack. The nine newly designed compounds had better rigid and flexible docking scores, free energy of binding and intermolecular interactions with survivin at BIR domain than the eight active inhibitors. Based on frontier molecular orbitals, OPE-3 was found to be the most reactive and less stable compound (0.13194 eV), followed by OPE-4 and OPE-9. The global descriptive parameters showed that OPE-3 had highest softness value (7.5245 eV) while OPE-8 recorded the maximum hardness value (0.08486 eV). The well-validated QSAR model also showed that OPE-3, OPE-7 and OPE-8 had the most significant bioactivity of all the inhibitors. This study thus provides new insight into the design of compounds capable of modulating the activity of survivin.

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All data generated in this study have been included in the article and supplementary material

Abbreviations

DFT:

Density functional theory

PDB:

Protein data bank

QSAR:

Quantitative structure active relationship

BIR:

Baculovirus IAP repeat

SMAC:

Secondary mitochondria activator of caspase

DIABLO:

Direct IAP binding protein with low pI

IAP:

Inhibitors of the apoptotic proteins

OPLS:

Optimized potentials for liquid simulations

HOMO:

Highest occupied molecular orbital

LUMO:

Lowest unoccupied molecular orbital

IFD:

Induced fit docking

XP:

Extra precision

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Acknowledgements

The authors acknowledge the technical support received from Computational Biologists at Bioinformatics and Molecular Biology Unit, Department of Biochemistry, Federal University of Technology, Akure, Ondo State, Nigeria.

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Authors and Affiliations

  1. Bioinformatics and Molecular Biology Unit, Department of Biochemistry, Federal University of Technology Akure, P.M.B. 704, Akure, 360001, Ondo, Nigeria

    Olusola Olalekan Elekofehinti, Opeyemi Iwaloye & Ibukun Mary Folorunso

  2. Nano-Gene and Drug Delivery Group, Department of Biochemistry, School of Life Science, University of Kwazulu Natal, Durban, 4000, South Africa

    Femi Olawale

  3. Department of Biochemistry, University of Lagos, Lagos, Nigeria

    Femi Olawale

  4. Federal University of Technology Akure, P.M.B. 704, Akure, 360001, Ondo, Nigeria

    Prosper Obed Chukwuemeka

Authors
  1. Olusola Olalekan Elekofehinti
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  2. Opeyemi Iwaloye
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  3. Femi Olawale
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  4. Prosper Obed Chukwuemeka
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  5. Ibukun Mary Folorunso
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Contributions

OE: Project drafting, provision of resources for research and manuscript revision; IO: Conception and implementation of the in silico experiment, generation and analysis of data, interpretation of data and preparation of manuscript draft; OF: Project design, data acquisition and preparation of manuscript draft; PC: Manuscript draft and substantial manuscript revision; IMF: substantial manuscript revision. All authors read and approved the manuscript before submission.

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Correspondence to Opeyemi Iwaloye.

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Elekofehinti, O.O., Iwaloye, O., Olawale, F. et al. Newly designed compounds from scaffolds of known actives as inhibitors of survivin: computational analysis from the perspective of fragment-based drug design. In Silico Pharmacol. 9, 47 (2021). https://doi.org/10.1007/s40203-021-00108-8

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