Side-chain conformational analysis

B. Conformational free energy analysis Side chains vs. all atom optimization... 

Cromakalim (137) is a potassium channel activator commonly used as an antihypertensive agent (107). The rationale for the design of cromakalim is based on P-blockers such as propranolol (115) and atenolol (123). Conformational restriction of the propanolamine side chain as observed in the cromakalim chroman nucleus provides compounds with desired antihypertensive activity free of the side effects commonly associated with P-blockers. Enantiomerically pure cromakalim is produced by resolution of the diastereomeric (T)-a-meth5lben2ylcarbamate derivatives. X-ray crystallographic analysis of this diastereomer provides the absolute stereochemistry of cromakalim. Biological activity resides primarily in the (—)-(33, 4R)-enantiomer [94535-50-9] (137) (108). In spontaneously hypertensive rats, the (—)-(33, 4R)-enantiomer, at dosages of 0.3 mg/kg, lowers the systoHc pressure 47%, whereas the (+)-(3R,43)-enantiomer only decreases the systoHc pressure by 14% at a dose of 3.0 mg/kg. 

FI Schrauber, F Eisenhaber, P Argos. Rotamers To be or not to be An analysis of ammo acid side-chain conformations m globular proteins. J Mol Biol 230 592-612, 1993. 

MJ McGregor, SA Islam, MJE Sternberg. Analysis of the relationship between side-chain conformation and secondary structure m globular proteins. J Mol Biol 198 295-310, 1987. 

Analysis and prediction of side-chain conformation have long been predicated on statistical analysis of data from protein structures. Early rotamer libraries [91-93] ignored backbone conformation and instead gave the proportions of side-chain rotamers for each of the 18 amino acids with side-chain dihedral degrees of freedom. In recent years, it has become possible to take account of the effect of the backbone conformation on the distribution of side-chain rotamers [28,94-96]. McGregor et al. [94] and Schrauber et al. [97] produced rotamer libraries based on secondary structure. Dunbrack and Karplus [95] instead examined the variation in rotamer distributions as a function of the backbone dihedrals ( ) and V /, later providing conformational analysis to justify this choice [96]. Dunbrack and Cohen [28] extended the analysis of protein side-chain conformation by using Bayesian statistics to derive the full backbone-dependent rotamer libraries at all... 

E Benedetti, G Morelh, G Nemethy, HA Scheraga. Statistical and energetic analysis of side-chain conformations m oligopeptides. Int J Peptide Pi otem Res 22 1-15, 1983. 

Peters, D., and J. Peters. 1982c. Quantum Theory of the Structure and Bonding in Proteins Part 12. Conformational analysis of side chains and the ethyl group as a model side chain. J. Mol. Struct. (Theochem) 88, 137-156. 

In order to obtain more information about the receptor-active conformation of muscimol, X-ray structure analysis, and ab initio quantum chemical studies have been applied to this compound (14). The flexibility of muscimol exclusively resides in the side chain (O-C-C-N bond) and a calculated potential energy curve for the rotation about this bond of muscimol in its zwitterionic form is shown in Fig. 3. These studies have demonstrated that in order for muscimol to obtain the conformation displayed by THIP, a conformational energy of 8.9 kcal/mol is required, which makes it less likely that the receptor-active conformation of muscimol corresponds to that of THIP. On the contrary, the conformation of THIP seems to mimic a high-energy conformation of muscimol as shown on the energy curve in Fig. 3, where the dihedral angles corresponding to the solid-state conformations of the muscimol zwitterion and the THIP cation are denoted. 

---