title: Some binding-related drug properties are dependent on thermodynamic signature.
abstract: The binding affinity is determined by the Gibbs energy of binding (ΔG) which is the sum of enthalpic (ΔH) and entropic (-TΔS) contributions. Because the enthalpy and entropy contribute in an additive way to the binding energy, the same binding affinity can be achieved by many different combinations of enthalpic and entropic contributions; however, do compounds with similar binding affinities but different thermodynamic signatures (i.e., different ΔH, -TΔS combinations) exhibit the same functional effects? Are there characteristics of compounds that can be modulated by modifying their thermodynamic signatures? In this paper, we consider the minimization of unwanted conformational effects arising during the development of CD4/gp120 inhibitors, a new class of HIV-1 cell entry inhibitors. Competitive inhibitors of protein/protein interactions run the risk of triggering the very same signals that they are supposed to inhibit. Here, we show that for CD4/gp120 inhibitors, the magnitude of those unwanted effects is related to the proportion in which the enthalpy and entropy changes contribute to the binding affinity. The thermodynamic optimization plot (TOP) previously proposed to optimize binding affinity can also be used to obtain appropriate enthalpy/entropy combinations for drug candidates.
authors.affiliation: Department of Biology, The Johns Hopkins University, 3400 North Charles, Baltimore, MD 21218, USA.
authors.forename: Arne
authors.initials: A
authors.lastname: Schön
authors.forename: Navid
authors.initials: N
authors.lastname: Madani
authors.forename: Amos B
authors.initials: AB
authors.lastname: Smith
authors.forename: Judith M
authors.initials: JM
authors.lastname: Lalonde
authors.forename: Ernesto
authors.initials: E
authors.lastname: Freire
mesh_terms: D015704:CD4 Antigens / Q000737:chemistry / Q000378:metabolism; D006678:HIV / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000378:metabolism; D023581:HIV Fusion Inhibitors / Q000737:chemistry*; D006801:Humans; D010070:Oxalates / Q000737:chemistry; D010880:Piperidines / Q000737:chemistry; D011485:Protein Binding; D013816:Thermodynamics
chemical_list: D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D023581:HIV Fusion Inhibitors; C514246:N-(4-chlorophenyl)-N'-(2,2,6,6-tetramethylpiperidin-4-yl)oxalamide; D010070:Oxalates; D010880:Piperidines