Ferreira M. M. C., Kiralj R., "QSAR and Conformational Study of 1H-Indole-3-Acetic Acids with Auxin Activity".  Caxambu, MG, 23-26/11/2003: 12° Simpósio Brasileiro de Química Teórica (XII SBQT) [12th Brazilian Symposium of Theoretical Chemistry], Livro de Resumos [Book of Abstracts], (2003) P150. Poster P150.

QSAR AND CONFORMATIONAL STUDY OF 1H-INDOLE-3-
ACETIC ACID WITH AUXIN ACTIVITY

Márcia M. C. Ferreira (PQ), Rudolf Kiralj (PQ)
rudolf@iqm.unicamp.br
Instituto de Química - UNICAMP, Campinas SP, 13084-971 Brazil.

Palavras-chave: QSAR, auxins, chemometrics

               1H-Indole-3-acetic  acid   (IAA,  Scheme)   and   its  derivatives  are  among  the  most
important  plant-growth  regulation  hormones  from auxin class.   Their  Quantitative  Structure-
Activity Relationships  (QSAR)  are not straitforward,   mainly  due to the lack of 3D structure of
a receptor which has been determined just recently for a complex of auxin ABP1  (auxin binding
protein 1) with 1-naphthalenic acid (NAA, Scheme), and intrinsic auxin properties.   IAA consists
of  planar heteroaromatic indole ring,   and the side chain acetate group which can adopt  a few
distinct orientations  with  respect to the ring.   Usually IAA auxins are limited to derivatives  with
small substituents  at five substitution positions  at the indole ring.
               This work deals with QSAR and conformational properties of 22 IAAs,  11/15 of  which
has  measured  straight-growth  promoting  activities  on  Avena Sativa  L.  coleoptiles  [1]:   the
optimal coleoptile elongation L, the half-optimum concentration c, and the optimal concentration
m,   all relative to IAA.   Conformers close to IAA  in crystalline state were selected  for geometry
optimization    at   ab  initio  B3LYP 6-31G**   and   MMFF94   level,   and  various   topological,
electrotopological,  steric,  electronic  and  lipophilicity  molecular  descriptors  were  calculated.
Selected descriptors were then analyzed by means of  Hierarchical Cluster Analysis (HCA)  and
Principal Component Analysis (PCA).  Partial Least Squares (PLS), Principal Component (PCR)
and  Multiple Linear (MLR) regression models were built and validated for  estimation/prediction
of the biological activities logL,  logc and logm.   Twenty-two ABP1 – auxin complexes built from
ABP1 – NAA   complex   crystal  structure  [2],   and  their  geometries  optimized   by   MMFF94.
                The  regression  models   were  based  on    11  (alkylated)  and    15  (alkylated  and
fluorinated) IAAs in the training set.   In general,   PLS and PCR models are similar,   while MLR
models  are  worse.    Predicted   activities   agree  reasonable   with  expectations  and  current
knowledge on IAA auxin activity.   Molecular graphics on  ABP1-NAA/IAA  complexes  give  more
mechanistic insight into  ABP1 – auxin  binding,   which is specially related to  –logc.   HCA  and
PCA  analyses  show discrimination of  the  auxins  with  respect  to  their activity and molecular
characteristics.  Conformation of an IAA molecule regarding to the CH₂CO₂H  side chain plays a
very important rule in  IAA  behavior.   Remarkable differences in torsion angles   T1 (C2-C3-C8-
C9)   and   T2 (C3-C8-C9-O10)   can be observed for IAA  in free state,   in  its crystal and some
crystals of molecular complexes including  IAA,   and in modeled ABP1 – IAA  complex.   Besides,
due to complexation of Zn2+ ion from ABP1 with IAAs, T1 and T2 show systematic changes with
respect to free or crystalline state of these  IAAs.   T1  and  T2  are related to biological activities
and molecular properties at qualitative and even quantitative  level.   (FAPESP)
 



Scheme. 1H-indole-3-acetic acid and 1-naphthalenic acid

[1] B. Nigovic et al., Acta Cryst. B56 (2000) 94.
[2] E.-J. Woo et al., EMBO J. 21 (2002) 2877.