Molecular dynamics simulation and binding free energy studies of novel leads belonging to the benzofuran class inhibitors of Mycobacterium tuberculosis Polyketide Synthase 13

Abstract

In this work, the binding mechanism of new Polyketide Synthase 13 (Pks13) inhibitors has been studied through molecular dynamics simulation and free energy calculations. The drug Tam1 and its analogs, belonging to the benzofuran class, were submitted to 100 ns simulations, and according to the results obtained for root mean square deviation, all the simulations converged from approximately 30 ns. For the analysis of backbone flotation, the root mean square fluctuations were plotted for the Cα atoms; analysis revealed that the greatest fluctuation occurred in the residues that are part of the protein lid domain. The binding free energy value (ΔG_bind) obtained for the Tam16 lead molecule was of −51.43 kcal/mol. When comparing this result with the ΔG_bind values for the remaining analogs, the drug Tam16 was found to be the highest ranked: this result is in agreement with the experimental results obtained by Aggarwal and collaborators, where it was verified that the IC₅₀ for Tam16 is the smallest necessary to inhibit the Pks13 (IC₅₀ = 0.19 μM). The energy decomposition analysis suggested that the residues which most interact with inhibitors are: Ser1636, Tyr1637, Asn1640, Ala1667, Phe1670, and Tyr1674, from which the greatest energy contribution to Phe1670 was particularly notable. For the lead molecule Tam16, a hydrogen bond with the hydroxyl of the phenol not observed in the other analogs induced a more stable molecular structure. Aggarwal and colleagues reported this hydrogen bonding as being responsible for the stability of the molecule, optimizing its physic-chemical, toxicological, and pharmacokinetic properties.

Keywords:

• molecular dynamics
• free energy
• benzofuran
• inhibitors
• Pks13
• M. tuberculosis

Abbreviations:

• CoA, coenzyme A
• FAS, fatty acid synthase
• GAFF, general amber force field
• GB, generalized born
• HB, hydrogen bonds
• INH, isoniazid
• KatG, catalase-peroxidase
• MD, molecular dynamics
• MDR, multi-drug resistant
• MM/GBSA, molecular mechanics/generalized-born surface area
• NAD, nicotinamide adenine dinucleotide
• NS, nanoseconds
• PCA, acyl carrier protein
• Pks13, polyketide synthase 13
• RESP, restrained electrostatic potential
• RMSD, root mean square deviation
• RMSF, root mean square fluctuations
• TB, tuberculosis
• TE, C-terminal thioesterase
• XDR, extensively drug resistant
• ΔE_ele, electrostatic contribution
• ΔE_eletrostatic, electrostatic contributions
• ΔE_internal, internal energy
• ΔE_MM, energy of the molecular mechanics
• ΔE_vdw, Van Der Waals contributions
• ΔG_GB, polar contributions
• ΔG_nonpol, non-polar contributions
• ΔG_solv, energy of desolvation
• ΔG_pol, polar solvation contribution
• CNPq, National Council for Scientific and Technological Development

Acknowledgments

A. M. J. C. Neto and Jorddy N. Cruz appreciate the support of the Federal University of Pará and the National Council for Scientific and Technological Development (CNPq).