TY - JOUR
T1 - Thermodynamic rules for the design of high affinity HIV-1 protease inhibitors with adaptability to mutations and high selectivity towards unwanted targets
AU - Ohtaka, Hiroyasu
AU - Muzammil, Salman
AU - Schön, Arne
AU - Velazquez-Campoy, Adrian
AU - Vega, Sonia
AU - Freire, Ernesto
N1 - Funding Information:
Supported by grants from the National Institutes of Health GM 57144 and GM56550 and the National Science Foundation MCB-9816661.
PY - 2004/9
Y1 - 2004/9
N2 - Protease inhibitors are key components in the chemotherapy of HIV-1 infection. However, the long term efficacy of antiretroviral therapies is hampered by issues of patient compliance often associated with the presence of severe side effects, and above all by the appearance of drug resistance. The development of new protease inhibitors with high potency, low susceptibility to mutations and minimal affinity for unwanted targets is an urgent goal. The engineering of these adaptive inhibitors requires identification of the critical determinants of affinity, adaptability, and selectivity. Analysis of the binding database for existing clinical and experimental inhibitors has allowed us to address the following questions in a quantitative fashion: (1) Is there an optimal binding affinity? Or, are the highest affinity inhibitors necessarily the best inhibitors? (2) What is the dependence of optimal affinity on adaptability and selectivity? (3) What are the determinants of adaptability to mutations associated with drug resistance? (4) How selectivity against unwanted targets can be improved? It is shown that the optimal affinity is a function of the effective target concentration and the desired adaptability and selectivity factors. Furthermore, knowledge of the enthalpic and entropic contributions to the binding affinity to the wild type provides a way of anticipating the response of an inhibitor to mutations associated with drug resistance, and therefore, a valuable guideline for optimization.
AB - Protease inhibitors are key components in the chemotherapy of HIV-1 infection. However, the long term efficacy of antiretroviral therapies is hampered by issues of patient compliance often associated with the presence of severe side effects, and above all by the appearance of drug resistance. The development of new protease inhibitors with high potency, low susceptibility to mutations and minimal affinity for unwanted targets is an urgent goal. The engineering of these adaptive inhibitors requires identification of the critical determinants of affinity, adaptability, and selectivity. Analysis of the binding database for existing clinical and experimental inhibitors has allowed us to address the following questions in a quantitative fashion: (1) Is there an optimal binding affinity? Or, are the highest affinity inhibitors necessarily the best inhibitors? (2) What is the dependence of optimal affinity on adaptability and selectivity? (3) What are the determinants of adaptability to mutations associated with drug resistance? (4) How selectivity against unwanted targets can be improved? It is shown that the optimal affinity is a function of the effective target concentration and the desired adaptability and selectivity factors. Furthermore, knowledge of the enthalpic and entropic contributions to the binding affinity to the wild type provides a way of anticipating the response of an inhibitor to mutations associated with drug resistance, and therefore, a valuable guideline for optimization.
KW - AIDS
KW - Adaptive inhibitors
KW - Binding thermodynamics
KW - Drug resistance
KW - Enzyme inhibition
KW - HIV-1 protease
KW - Isothermal titration calorimetry
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U2 - 10.1016/j.biocel.2004.02.021
DO - 10.1016/j.biocel.2004.02.021
M3 - Review article
C2 - 15183345
AN - SCOPUS:2942557079
VL - 36
SP - 1787
EP - 1799
JO - International Journal of Biochemistry
JF - International Journal of Biochemistry
SN - 1357-2725
IS - 9
ER -