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Molecular Recognition of Azelaic Acid and Related Molecules with DNA Polymerase I Investigated by Molecular Modeling Calculations

Abstract

Molecular recognition has central role on the development of rational drug design. Binding affinity and interactions are two key components which aid to understand the molecular recognition in drug-receptor complex and crucial for structure-based drug design in medicinal chemistry. Herein, we report the binding affinity and the nonbonding interactions of azelaic acid and related compounds with the receptor DNA polymerase I (2KFN). Quantum mechanical calculation was employed to optimize the modified drugs using B3LYP/6-31G(d,p) level of theory. Charge distribution, dipole moment and thermodynamic properties such as electronic energy, enthalpy and free energy of these optimized drugs are also explored to evaluate how modifications impact the drug properties. Molecular docking calculation was performed to evaluate the binding affinity and nonbonding interactions between designed molecules and the receptor protein. We notice that all modified drugs are thermodynamically more stable and some of them are more chemically reactive than the unmodified drug. Promise in enhancing hydrogen bonds is found in case of fluorine-directed modifications as well as in the addition of trifluoroacetyl group. Fluorine participates in forming fluorine bonds and also stimulates alkyl, pi-alkyl interactions in some drugs. Designed drugs revealed increased binding affinity toward 2KFN. A1, A2 and A3 showed binding affinities of −8.7, −8.6 and −7.9 kcal/mol, respectively against 2KFN compared to the binding affinity −6.7 kcal/mol of the parent drug. Significant interactions observed between the drugs and Thr358 and Asp355 residues of 2KFN. Moreover, designed drugs demonstrated improved pharmacokinetic properties. This study disclosed that 9-octadecenoic acid and drugs containing trifluoroacetyl and trifluoromethyl groups are the best 2KFN inhibitors. Overall, these results can be useful for the design of new potential candidates against DNA polymerase I.

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Abbreviations

AzA:

Azelaic acid

DFT:

Density functional theory

ADMET:

Absorption, distribution, metabolism, excretion, toxicity

QM:

Quantum mechanics

CASTp:

Computed Atlas of Surface Topography of proteins

SDF:

Structure Data File

SMILES:

Simplified molecular-input line-entry system

HOMO:

Highest occupied molecular orbital

LUMO:

Lowest unoccupied molecular orbital

hERG:

Human ether-a-go-go-related gene

BBB:

Blood brain barrier

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Acknowledgments

We are grateful to our donors who supported to build a computational platform in Bangladesh http://grc-bd.org/donate/.

Author’s Contribution

MAH, MGS and MAKK conceived the idea. MAH, MGS, MAKK and MMH designed the drugs. JS performed the quantum calculations. JS, AMK and AR performed the molecular docking, ADME calculations, data collection and draft writing. All authors read and approved the manuscript.

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This research does not receive any external funding.

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Correspondence to Mohammad A. Halim.

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Shawon, J., Khan, A.M., Rahman, A. et al. Molecular Recognition of Azelaic Acid and Related Molecules with DNA Polymerase I Investigated by Molecular Modeling Calculations. Interdiscip Sci Comput Life Sci 10, 525–537 (2018). https://doi.org/10.1007/s12539-016-0186-3

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Keywords

  • Rational drug design
  • Azelaic acid
  • Acne
  • DNA polymerase I
  • Density functional theory
  • Nonbonding interactions
  • Molecular docking