The Impact of Binding Thermodynamics on Medicinal Chemistry Optimizations

Abstract

Ligand binding thermodynamics has been attracted considerable interest in the past decade owing to the recognized relation between binding thermodynamic profile and the physicochemical and druglike properties of compounds. In this review, the relation between optimization strategies and ligand properties is presented based on the structural and thermodynamic analysis of ligand–protein complex formation. The control of the binding thermodynamic profile is beneficial for the balanced affinity and physicochemical properties of drug candidates, and early phase optimization gives more opportunity to this control.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Notes

ΔG: Binding free energy; ΔH: Binding enthalpy; BEI: Binding efficiency index; EE: Enthalpic efficiency; HA: Heavy atoms; HA_pol: Polar heavy atoms; LE: Ligand efficiency; LELP: Lipophilicity corrected ligand efficiency; LLE: Ligand lipophilicity efficiency; LLE_AT: Ligand lipophilicity efficiency (as defined in [45]); MW: molecular weight; pIC₅₀ : -log(IC₅₀); pK_i: -log(K_I): SILE: Size-independent ligand efficiency.

Additional information

Funding

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.