This classical QSAR study mainly focused on physiochemical descriptors. The
descriptors used by first classical QSAR model are in the following of B1 p
(Sterimol width parameter as the smallest width along Z axis; p indicates para
position), L o (Sterimol length parameter as the maximum length along the X axis),
MR p (molar refractivity impact in the para position), MR m (molar refractivity
impact in the meta position), p m (lipophilicity substitution constant). The descriptors used by second classical QSAR model are B1 p , B5 o (width parameter defined
as maximum width from X axis), MR p , B1 m, and p p . The MSA involved use of
molecular shape descriptors (DIFFV, COSV, NCOSV, Fo, Shape RMS) in addition
to electronic (dipol-mag and Sr), spatial (radius of gyration, Jurs descriptors, area,
PMI-mag, density, V m ), thermodynamic (ALogP, ALogP98, MolRef, MR, LogP)
and structural (H-bond donor, H-bond acceptor, rotatable bonds) descriptors.
Descriptors used by MSA are Fo (common overlap steric volume descriptor),
MolRef (atom type molar refractivity), JursDPSA_3 (difference in atomic
charge-weighted surface area), JursFPSA_1 (fractional charged partial positive
surface area), LogP (partition coefficient) and JursPPSA_3 (atomic charge-weighted
positive solvent-accessible surface area). Combined set descriptors (classical QSAR
and MSA) include B1 p , p p, B1 o and V m (molecular volume inside the contact
surface). The entire data set consists of 29 compounds which are divided into
training set (n = 22) and test set (n = 7) by using k-means clustering. All the
models have predictive R
2 more than 0.5, thus passing the basic criteria.
Classical QSAR with physiochemical descriptors was found to be the best model
based on r m(overall)
2
(0.733) and R p
2 (0.767). It was observed through this study that
(1) unsubstituted ortho position is desirable; (2) moderate hydrophobicity and
volume at meta position of the phenyl may enhance the PfDHODH inhibitory
activity; (3) para substitution is essential for inhibition with volume and
hydrophobicity to be high but restricted.
Molecular docking was performed using LigandFit module under Discovery
studio 2.1. Figure 22 shows the general 3D interactions of various polar and
non-polar residues with the 5-methyl-N-phenyl- [1, 2, 4] triazolo[1,5-a]pyrimidin7-amine. It was observed that the p-position of the phenyl substitution can
accommodate hydrophobic groups with large volume. However, substitutions with
phenyl ring at p-position were not able to attain an optimal position causing a bump
with important amino acids such as His185 and Val532 [89]. Therefore, the substituents were restricted to non-aromatic groups such as CF 3 , OCF 3 , and CH 3
(Fig. 22).
Shah et al. reported 3D-QSAR on the same class of compounds. Thirty-five
molecules of triazolopyrimidine class were selected for this study and molecular
docking was performed using FlexX software in X-ray crystal structure with
PDBID 3I68 [90]. The docking results highlighted two important structural features, a hydrophobic (aromatic) region which should have planar arrangement and a
polar region. As reported by the other group, His185 and Arg265 played crucial
role in polar interactions. Amino acid residues responsible for van der Waals
interactions are Gly181, Cys184, His185, Phe188, Leu189, Phe227, Leu531, and
Val532. Phe188 forms p-p interactions and Phe227 forms edge-to-face p
210
S. Bhagat et al.
descriptors used by first classical QSAR model are in the following of B1 p
(Sterimol width parameter as the smallest width along Z axis; p indicates para
position), L o (Sterimol length parameter as the maximum length along the X axis),
MR p (molar refractivity impact in the para position), MR m (molar refractivity
impact in the meta position), p m (lipophilicity substitution constant). The descriptors used by second classical QSAR model are B1 p , B5 o (width parameter defined
as maximum width from X axis), MR p , B1 m, and p p . The MSA involved use of
molecular shape descriptors (DIFFV, COSV, NCOSV, Fo, Shape RMS) in addition
to electronic (dipol-mag and Sr), spatial (radius of gyration, Jurs descriptors, area,
PMI-mag, density, V m ), thermodynamic (ALogP, ALogP98, MolRef, MR, LogP)
and structural (H-bond donor, H-bond acceptor, rotatable bonds) descriptors.
Descriptors used by MSA are Fo (common overlap steric volume descriptor),
MolRef (atom type molar refractivity), JursDPSA_3 (difference in atomic
charge-weighted surface area), JursFPSA_1 (fractional charged partial positive
surface area), LogP (partition coefficient) and JursPPSA_3 (atomic charge-weighted
positive solvent-accessible surface area). Combined set descriptors (classical QSAR
and MSA) include B1 p , p p, B1 o and V m (molecular volume inside the contact
surface). The entire data set consists of 29 compounds which are divided into
training set (n = 22) and test set (n = 7) by using k-means clustering. All the
models have predictive R
2 more than 0.5, thus passing the basic criteria.
Classical QSAR with physiochemical descriptors was found to be the best model
based on r m(overall)
2
(0.733) and R p
2 (0.767). It was observed through this study that
(1) unsubstituted ortho position is desirable; (2) moderate hydrophobicity and
volume at meta position of the phenyl may enhance the PfDHODH inhibitory
activity; (3) para substitution is essential for inhibition with volume and
hydrophobicity to be high but restricted.
Molecular docking was performed using LigandFit module under Discovery
studio 2.1. Figure 22 shows the general 3D interactions of various polar and
non-polar residues with the 5-methyl-N-phenyl- [1, 2, 4] triazolo[1,5-a]pyrimidin7-amine. It was observed that the p-position of the phenyl substitution can
accommodate hydrophobic groups with large volume. However, substitutions with
phenyl ring at p-position were not able to attain an optimal position causing a bump
with important amino acids such as His185 and Val532 [89]. Therefore, the substituents were restricted to non-aromatic groups such as CF 3 , OCF 3 , and CH 3
(Fig. 22).
Shah et al. reported 3D-QSAR on the same class of compounds. Thirty-five
molecules of triazolopyrimidine class were selected for this study and molecular
docking was performed using FlexX software in X-ray crystal structure with
PDBID 3I68 [90]. The docking results highlighted two important structural features, a hydrophobic (aromatic) region which should have planar arrangement and a
polar region. As reported by the other group, His185 and Arg265 played crucial
role in polar interactions. Amino acid residues responsible for van der Waals
interactions are Gly181, Cys184, His185, Phe188, Leu189, Phe227, Leu531, and
Val532. Phe188 forms p-p interactions and Phe227 forms edge-to-face p
210
S. Bhagat et al.