Molecular docking and 3D-QSAR studies on β-phenylalanine derivatives as dipeptidyl peptidase IV inhibitors

Three-dimensional quantitative structure-activity relationship (3D-QSAR) and molecular docking studies were carried out to explore the binding of 73 inhibitors to dipeptidyl peptidase IV (DPP-IV), and to construct highly predictive 3D-QSAR models using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The negative logarithm of IC₅₀ (pIC₅₀) was used as the biological activity in the 3D-QSAR study. The CoMFA model was developed by steric and electrostatic field methods, and leave-one-out cross-validated partial least squares analysis yielded a cross-validated value (r_cv² {\hbox{r}}_{{\rm{cv}}}^{\rm{2}} ) of 0.759. Three CoMSIA models developed by different combinations of steric, electrostatic, hydrophobic and hydrogen-bond fields yielded significant r_cv² {\hbox{r}}_{{\rm{cv}}}^{\rm{2}} values of 0.750, 0.708 and 0.694, respectively. The CoMFA and CoMSIA models were validated by a structurally diversified test set of 18 compounds. All of the test compounds were predicted accurately using these models. The mean and standard deviation of prediction errors were within 0.33 and 0.26 for all models. Analysis of CoMFA and CoMSIA contour maps helped identify the structural requirements of inhibitors, with implications for the design of the next generation of DPP-IV inhibitors for the treatment of type 2 diabetes.     

A molecular dynamics study on opioid activities of biphalin molecule

Molecular dynamics simulations of the biphalin molecule, (Tyr-D-Ala-Gly-Phe-NH)₂, and the active tetrapeptide hydrazide, Tyr-D-Ala-Gly-Phe-NH-NH₂ were performed to investigate the cause of the increased μ and δ receptor binding affinities of the former over the latter. The simulation results demonstrate that the acylation of the two equal tetrapeptide fragments of biphalin produces the constrained hydrazide bridges C₄^a - C₄￠- N₉ - N₁₀ {\hbox{C}}_4^{\alpha } - {{\hbox{C}}_4}\prime - {{\hbox{N}}_9} - {{\hbox{N}}_{{10}}} and N₉ - N₁₀ - C₅￠- C₅^a {{\hbox{N}}_9} - {{\hbox{N}}_{{10}}} - {{\hbox{C}}_5}\prime - {\hbox{C}}_5^{\alpha } , which in turn increase the opportunity of conformations for binding to μ or δ receptors. Meanwhile, the connection of the two active tetrapeptide fragments of biphalin also results in the constrained side chain torsion angle χ² at one of the two residues Phe. This constrained side chain torsion angle not only significantly increases the δ receptor binding affinity but also makes most of the δ receptor binding conformations of biphalin bind to the δ receptor through the fragment containing the mentioned residue Phe.     

CoMFA and CoMSIA analyses on 4-oxo-1,4-dihydroquinoline and 4-oxo-1,4-dihydro-1,5-, -1,6- and -1,8-naphthyridine derivatives as selective CB2 receptor agonists

Novel classes of CB2 agonists based on 4-oxo-1,4-dihydroquinoline and 4-oxo-1,4-dihydro-1,5-, -1,6- and -1,8-naphthyridine scaffolds have shown high binding affinity toward CB2 receptor and good selectivity over CB1. A computational study of comparative molecular fields analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) was performed, in order to identify the key structural features impacting their binding affinity. The final CoMSIA model resulted to be the more predictive, showing $ r_{ncv}^2 = 0.84 $ , $ r_{cv}^2 = ~0.619 $ , SEE?=?0.369, and $ r_{pred}^2 = 0.75 $ . The study provides useful suggestions for the synthesis of new selective analogues with improved affinity.     

Hologram and 3D-quantitative structure toxicity relationship studies of azo dyes

Amino azobenzenes are important dyes in the food and textile industry but their application is limited due to their mutagenicity. Computational modeling techniques were used to help understand the factors responsible for mutagenicity, and several quantitative structure toxicity relationship (QSTR) models have been derived. HQSTR (hologram QSTR) analyses indicated that different substituents at sites on both rings contribute to mutagenicity. Fragment parameters such as bond (B) and connectivity(C), as well as donor-acceptor (DA)-based model provide significant results (q² = 0.59, r² = 0.92, ) explaining these harmful effect. HQSTR results indicated that a bulky group at ring “Y” and small group at ring “X” might help to decrease mutagenicity. 3D-QSTR based on comparative molecular field analyses (CoMFA) and comparative molecular similarity index analyses (CoMSIA) are also in agreement with HQSTR. The 3D QSTR studies reveal that steric and electrostatic field effects have a strong relationship with mutagenicity (for CoMFA: q² = 0.51, r² = 0.95, and for CoMSIA: q² = 0.51, r² = 0.93 and ). In summary, negative groups and steric bulk at ring “Y” and small groups at carbon-3 of ring “X” might be helpful in reducing the mutagenicity of azo dyes.     

3D-QSAR studies of triazolopyrimidine derivatives of <Emphasis Type="Italic">Plasmodium falciparum</Emphasis> dihydroorotate dehydrogenase inhibitors using a combination of molecular dynamics,docking, and genetic algorithm-based methods

A series of 35 triazolopyrimidine analogues reported as Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors were optimized using quantum mechanics methods, and their binding conformations were studied by docking and 3D quantitative structure–activity relationship studies. Genetic algorithm-based criteria was adopted for selection of training and test sets while maintaining structural diversity of training and test sets, which is also very crucial for model development and validation. Both the comparative molecular field analyses ( q_\textLOO² = 0.841 q_{\text{LOO}}^2 = 0.{841} , r_\textncv² = 0.99 r_{\text{ncv}}^2 = 0.{99} ) and comparative molecular similarity indices analyses ( q_\textLOO² = 0.757 q_{\text{LOO}}^2 = 0.{757} , r_\textncv² = 0.943 r_{\text{ncv}}^2 = 0.{943} ) show excellent correlation and high predictive power. Furthermore, molecular dynamics simulations were performed to explore the binding mode of the two of the most active compounds of the series, 10 and 14. Harmonization in the two simulation results validate the analysis and therefore applicability of docking parameters based on crystallographic conformation of compound 14 bound to receptor molecule. This work provides useful information about the inhibition mechanism of this class of molecules and will assist in the design of more potent inhibitors of PfDHODH.     

Can the positive aromatic ring be as ��-electron donor in ��-halogen bond? A MP2 theoretical investigation on the unusual ��-halogen bond interaction between three-membered ring \left( {\hbox{BNN}} \right)_3^{+} and X1X2 (X1, X2?=?F, Cl, Br)

The unusual ??-halogen bond interactions are investigated between $ \left( {\hbox{BNN}} \right)_3^{+} $ and X1X2 (X1, X2?=?F, Cl, Br) employing MP2 at 6-311?+?G(2d) and aug-cc-pVDZ levels according to the ??CP (counterpoise) corrected potential energy surface (PES)?? method. The order of the ??-halogen bond interactions and stabilities of the complexes are obtained to be $ \left( {\hbox{BNN}} \right)_3^{+} \ldots {{\hbox{F}}_2} < \left( {\hbox{BNN}} \right)_3^{+} \ldots {\hbox{ClF < }}\left( {\hbox{BNN}} \right)_3^{+} \ldots {\hbox{C}}{{\hbox{l}}_2} < \left( {\hbox{BNN}} \right)_3^{+} \ldots {\hbox{BrCl}}\quad { < }\quad \left( {\hbox{BNN}} \right)_3^{+} \ldots {\hbox{B}}{{\hbox{r}}_2}\quad { < }\quad \left( {\hbox{BNN}} \right)_3^{+} \ldots {\hbox{BrF}}{.} $ at MP2/aug-cc-pVDZ level. The analyses of the Mulliken charge transfer, natural bond orbital (NBO), atoms in molecules (AIM) theory and electron density shifts reveal that the nature of the ??-halogen bond interaction in the complexes of ClF, BrF and BrCl might partly be charge transfer from the delocalized ??-HOMO orbital of $ \left( {\hbox{BNN}} \right)_3^{+} $ to X1X2. This result suggests that the positive aromatic ring $ \left( {\hbox{BNN}} \right)_3^{+} $ might act as a ??-electron donor to form the ??-halogen bond.

Growth yields and saturation constant of Desulfovibrio vulgaris in chemostat culture

Desulfovibrio vulgaris (strain Marburg) was grown on H₂ and sulfate as sole energy source in a chemostat limited by the sulfate supply. The biomass concentration and the sulfate concentration in the culture were determined as a function of the dilution rate. From the data a K _S (saturation constant) for sulfate of 10 M, a _max of 0.23 h^–1, and a of 13 g/mol were calculated. The organism was also grown in chemostat culture on H₂ and sulfite, H₂ and thiosulfate, and pyruvate (without sulfate). was found to be 35 g/mol, 36 g/mol, and Y _pyr ^max 10 g/mol. The growth yields are discussed with respect to ATP gains in dissimilatory sulfate reduction.     

Structure-based 3D-QSAR studies on thiazoles as 5-HT<Subscript>3</Subscript> receptor antagonists

Structure-based 3D-QSAR studies were performed on 20 thiazoles against their binding affinities to the 5-HT₃ receptor with comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The thiazoles were initially docked into the binding pocket of a human 5-HT_3A receptor homology model, constructed on the basis of the crystal structure of the snail acetylcholine binding protein (AChBP), using the GOLD program. The docked conformations were then extracted and used to build the 3D-QSAR models, with cross-validated values 0.785 and 0.744 for CoMFA and CoMSIA, respectively. An additional five molecules were used to validate the models further, giving satisfactory predictive values of 0.582 and 0.804 for CoMFA and CoMSIA, respectively. The results would be helpful for the discovery of new potent and selective 5-HT₃ receptor antagonists.      

A comparative study of the mechanism of Na+ and Cl? excretion by the gill ofMugil capito andFundulus heteroclitus: Effects of Stress

Summary In seawater (SW)-adaptedMugil andFundulus, gill effluxes of Na⁺ and of Cl^– and the simultaneously recorded transgill potential (P.D.) differ according to whether they are measured in stressed or rested animals.In rested animals of the two species, transfer to Ringer's solution considerably reduces the P.D. but not . InFundulus, is also decreased. Transfer of the two species from SW to fresh water (FW) reduces and by 75 to 85% and leads to a large inversion of P.D. When K⁺ is added to FW, a gill depolarization occurs, as well as a large increase of and .These results suggest that: 1) the P.D. originates primarily from the diffusion of cations, the gill permeability to Na⁺ ( ) being greater than that to Cl^– ( ), 2) a Cl^–/Cl^– exchange independent of P.D. is associated with the Cl^– pump; 3) Cl^– pump activity is linked to Na⁺/K⁺ exchange which in turn is associated to a Na⁺/Na⁺ exchange diffusion mechanism.In stressed individuals of the two species, the P.D. in SW, as well as the P.D. changes observed during transfer experiments, are considerably reduced. The decrease of and observed after transfer from SW to FW are also minimised. Changes are smaller inFundulus. The decrease of P.D. characterizing stressed animals may be at least in part due to a 3 to 4 fold increase of which becomes equal to in both species.As a result of stress, the K⁺-activated Na⁺ and Cl^– excretion mechanisms are totally inhibited inFundulus and partially so inMugil.Stress response seems more intense inFundulus and recovery from stress faster inMugil.     

Energy requirements of Adélie penguin (Pygoscelis adeliae) chicks

Summary The energy requirements of Adélie penguin (Pygoscelis adeliae) chicks were analysed with respect to body mass (W, 0.145–3.35 kg, n=36) and various forms of activity (lying, standing, minor activity, locomotion, walking on a treadmill). Direct respirometry was used to measure O₂ consumption ( ) and CO₂ production. Heart rate (HR, bpm) was recorded from the ECG obtained by both externally attached electrodes and implantable HR-transmitters. The parameters measured were not affected by hand-rearing of the chicks or by implanting transmitters. HR measured in the laboratory and in the field were comparable. Oxygen uptake ranged from in lying chicks to at maximal activity, RQ=0.76. Metabolic rate in small wild chicks (0.14–0.38 kg) was not affected by time of day, nor was their feeding frequency in the colony (Dec 20–21). Regressions of HR on were highly significant (p< 0.0001) in transmitter implanted chicks (n=4), and two relationships are proposed for the pooled data, one for minor activities ( ), and one for walking ( ). Oxygen consumption, mass of the chick (2–3 kg), and duration of walking (T, s) were related as , whereas mass-specific O₂ consumption was related to walking speed (S, m·s^-1) as .Abbreviations bpm beats per minute - D distance walked (m) - ECG electrocardiogram - HR heart rate (bpm) - ns number of steps - RQ respiratory quotient - S walking speed (m·s^-1) - T time walked (s) - W body mass (kg)     

Loss of ncm<Superscript>5</Superscript> and mcm<Superscript>5</Superscript> wobble uridine side chains results in an altered metabolic profile

Introduction

The Elongator complex, comprising six subunits (Elp1p-Elp6p), is required for formation of 5-carbamoylmethyl (ncm⁵) and 5-methoxycarbonylmethyl (mcm⁵) side chains on wobble uridines in 11 out of 42 tRNA species in Saccharomyces cerevisiae. Loss of these side chains reduces the efficiency of tRNA decoding during translation, resulting in pleiotropic phenotypes. Overexpression of hypomodified \( {\text {tRNA}_{{\rm s^{2} {\rm UUU}}}^{{\rm Lys}} , {\rm tRNA}_{{\rm s^{2} {\rm UUG}}}^{{\rm Gln }} \;{\rm and}\;{\rm tRNA}_{{\rm s^{2} {\rm UUC}}}^{{\rm Glu}}} \), which in wild-type strains are modified with mcm⁵s²U, partially suppress phenotypes of an elp3Δ strain.

Objectives

To identify metabolic alterations in an elp3Δ strain and elucidate whether these metabolic alterations are suppressed by overexpression of hypomodified \( {\text {tRNA}_{{\rm s^{2} {\rm UUU}}}^{{\rm Lys}} , {\rm tRNA}_{{\rm s^{2} {\rm UUG}}}^{{\rm Gln }} \;{\rm and}\;{\rm tRNA}_{{\rm s^{2} {\rm UUC}}}^{{\rm Glu}}} \).

Method

Metabolic profiles were obtained using untargeted GC-TOF-MS of a temperature-sensitive elp3Δ strain carrying either an empty low-copy vector, an empty high-copy vector, a low-copy vector harboring the wild-type ELP3 gene, or a high-copy vector overexpressing \( {\text {tRNA}_{{\rm s^{2} {\rm UUU}}}^{{\rm Lys}} , {\rm tRNA}_{{\rm s^{2} {\rm UUG}}}^{{\rm Gln }} \;{\rm and}\;{\rm tRNA}_{{\rm s^{2} {\rm UUC}}}^{{\rm Glu}}} \). The temperature sensitive elp3Δ strain derivatives were cultivated at permissive (30 °C) or semi-permissive (34 °C) growth conditions.

Results

Culturing an elp3Δ strain at 30 or 34 °C resulted in altered metabolism of 36 and 46 %, respectively, of all metabolites detected when compared to an elp3Δ strain carrying the wild-type ELP3 gene. Overexpression of hypomodified \( {\text {tRNA}_{{\rm s^{2} {\rm UUU}}}^{{\rm Lys}} , {\rm tRNA}_{{\rm s^{2} {\rm UUG}}}^{{\rm Gln }} \;{\rm and}\;{\rm tRNA}_{{\rm s^{2} {\rm UUC}}}^{{\rm Glu}}} \) suppressed a subset of the metabolic alterations observed in the elp3Δ strain.

Conclusion

Our results suggest that the presence of ncm⁵- and mcm⁵-side chains on wobble uridines in tRNA are important for metabolic homeostasis.

     

A Combined Patch-Clamp and Electrorotation Study of the Voltage- and Frequency-Dependent Membrane Capacitance Caused by Structurally Dissimilar Lipophilic Anions

Interactions of structurally dissimilar anionic compounds with the plasma membrane of HEK293 cells were analyzed by patch clamp and electrorotation. The combined approach provides complementary information on the lipophilicity, preferential affinity of the anions to the inner/outer membrane leaflet, adsorption depth and transmembrane mobility. The anionic species studied here included the well-known lipophilic anions dipicrylamine (DPA⁻), tetraphenylborate (TPB⁻) and [W₂(CO)₁₀(S₂CH)]⁻, the putative lipophilic anion and three new heterocyclic W(CO)₅ derivatives. All tested anions partitioned strongly into the cell membrane, as indicated by the capacitance increase in patch-clamped cells. The capacitance increment exhibited a bell-shaped dependence on membrane voltage. The midpoint potentials of the maximum capacitance increment were negative, indicating the exclusion of lipophilic anions from the outer membrane leaflet. The adsorption depth of the large organic anions DPA⁻, TPB⁻ and increased and that of W(CO)₅ derivatives decreased with increasing concentration of mobile charges. In agreement with the patch-clamp data, electrorotation of cells treated with DPA⁻ and W(CO)₅ derivatives revealed a large dispersion of membrane capacitance in the kilohertz to megahertz range due to the translocation of mobile charges. In contrast, in the presence of TPB⁻ and no mobile charges could be detected by electrorotation, despite their strong membrane adsorption. Our data suggest that the presence of oxygen atoms in the outer molecular shell is an important factor for the fast translocation ability of lipophilic anions.     

Pair wise binding affinity: 3D QSAR studies on a set of triazolo [1, 5-a] quinoxalines as antagonists of AMPA and KA receptors

The glutamate receptor system is implicated in the development and maintenance of epileptic seizures and it has been reported that compounds showing high affinity for both AMPA and KA binding sites are more potent anticonvulsants than compounds having selective affinity toward AMPA or KA receptor. These outcomes make such inhibitors future potential antiepileptic drugs. So, the pair wise binding affinity for AMPA and KA receptors inhibition was proposed by using the addition between biological activities of ligands. This approach for evaluation of pair wise binding affinity was exemplified using set of triazolo [1,5-a] quinoxaline for AMPA and KA receptors. The biological activity towards AMPA and KA receptors (expressed as -log IC_5O) was taken as a dependent variable for building CoMFA and CoMSIA models. The resulting models show the ways of increasing binding affinity to both AMPA and KA receptors as potential target for epilepsy. The statistically significant results show that pair wise CoMFA and CoMSIA models are better then individual models. The resulting cross-validated r²_CV value 0.806 for CoMFA is greater then 0.780 for CoMSIA pair wise model. The non-cross validated run giving a coefficient of determination r² value of 0.946 and 0.908 for CoMFA and CoMSIA respectively, provided a good correlation between the observed and computed affinities of the compounds.     

Determination of heteronuclear three-bond J-coupling constants in peptides by a simple heteronuclear relayed E.COSY experiment

Summary A simple heteronuclear relayed E.COSY pulse sequence with a minimum number of pulses is proposed for the quantitative determination of heteronuclear three-bond J-coupling constants in uniformly ¹³C-enriched polypeptide samples. Numerous heteronuclear three-bond coupling constants, including , , , and , can be determined for each residue from a single heteronuclear relayed E.COSY spectrum. Couplings relevant for stereospecific assignments as well as for the determination of dihedral angles in the amino acid backbone and in side chains are obtained. The method is demonstrated on the uniformly ¹³C-enriched decapeptide antamanide (-Val¹-Pro²-Pro³-Ala⁴-Phe⁵-Phe⁶-Pro⁷-Pro⁸-Phe⁹-Phe¹⁰-).     

Transition from octahedral to tetrahedral geometry causes the activation or inhibition by Zn<Superscript>2+</Superscript> of <Emphasis Type="Italic">Pseudomonas aeruginosa</Emphasis> phosphorylcholine phosphatase

Pseudomonas aeruginosa phosphorylcholine phosphatase (PchP) catalyzes the hydrolysis of phosphorylcholine, which is produced by the action of hemolytic phospholipase C on phosphatidylcholine or sphyngomielin, to generate choline and inorganic phosphate. Among divalent cations, its activity is dependent on Mg²⁺ or Zn²⁺. Mg²⁺ produced identical activation at pH 5.0 and 7.4, but Zn²⁺ was an activator at pH 5.0 and became an inhibitor at pH 7.4. At this higher pH, very low concentrations of Zn²⁺ inhibited enzymatic activity even in the presence of saturating Mg²⁺ concentrations. Considering experimental and theoretical physicochemical calculations performed by different authors, we conclude that at pH 5.0, Mg²⁺ and Zn²⁺ are hexacoordinated in an octahedral arrangement in the PchP active site. At pH 7.4, Mg²⁺ conserves the octahedral coordination maintaining enzymatic activity. The inhibition produced by Zn²⁺ at 7.4 is interpreted as a change from octahedral to tetrahedral coordination geometry which is produced by hydrolysis of the [ \textZn ²⁺ \textL ₂ ^{- 1} \textL ₂⁰ ( \textH ₂ \textO ) ₂ ] \left[ {{\text{Zn}}^{ 2+ } {\text{L}}_{ 2}^{ - 1} {\text{L}}_{ 2}^{0} \left( {{\text{H}}_{ 2} {\text{O}}} \right)_{ 2} } \right] complex.     

(H)NCAHA and (H)CANNH experiments for the determination of vicinal coupling constants related to the ϕ-torsion angle

Summary A set of three-dimensional triple-resonance experiments is described which provide , , and coupling constants. The pulse sequences generate E.COSY-like multiplet patterns and comprise a magnetization transfer from the amide proton to the α-proton or vice versa via the directly bound heteronuclei. For residues with the ¹H^α spin resonating close to the H₂O signal, a modified HNCA experiment can be employed to measure the vicinal ¹H^N,¹H^α couplings. Ambiguities associated with the conversion of values into ϕ-angle constraints for protein structure determination can be resolved with the knowledge of the heteronuclear ³J-couplings. In favourable cases, stereospecific assignments of glycine α-protons can be obtained by employing the experiments described here in combination with NOE data. The methods are applied to flavodoxin from Desulfovibrio vulgaris.     

Genetic effects on wood quality traits of plantation-grown white spruce (Picea glauca) and their relationships with growth

Clonal repeatabilities on individual tree (H_i² H_i^2 ) and clonal mean (H_{[`(C)]</sub> <sup>2</sup> H_{{\overline C }}^2 ) bases for growth (14-year height and volume), wood quality traits (latewood proportion, wood density, fiber length, and microfibril angle), and genotypic correlations among the traits were estimated, using 30 white spruce (Picea glauca [Moench] Voss) clones from six full-sib families (five per family). These families were selected from a clonally replicated test to represent different early growth categories: fast, moderate, and slow. Wood increment cores of the 30 clones were collected from two contrasting sites at age 19 years. For growth traits, in contrast to most wood quality traits, more genetic variation was accounted for by clone within family than by family within growth category. Both growth and wood quality traits appear to be under moderate genetic control, with [^(H)]<sub>i</sub><sup>2</sup> = 0.20 - 0.36 \widehat{H}_i^2 = 0.20 - 0.36 and [^(H)]<sub>[`(C)]} ² = 0.70 - 0.83 \widehat{H}_{{\overline C }}^2 = 0.70 - 0.83 . The only exception was microfibril angle ( [^(H)]_i² = 0.10  \textand  [^(H)]_[`(C)] ² = 0.34 \widehat{H}_i^2 = 0.10\;{\text{and}}\;\widehat{H}_{{\overline C }}^2 = 0.34 ). Generally, faster growth resulted in a significantly lower latewood proportion and lower overall wood density. Selection for faster growth does not appear to impact on either fiber length or microfibril angle. Among the wood quality traits, significant genotypic association was observed only between latewood proportion and wood density. Despite the generally negative association between growth and wood density among families, several fast-growing clones maintained above-average density. This implies that, by adopting multiclonal forestry, one can simultaneously improve growth and wood density.     

Elucidation of binding mode and three dimensional quantitative structure–activity relationship studies of a novel series of protein kinase B/Akt inhibitors

Protein kinase B (PKB; also known as Akt kinase) is located downstream in the PI-3 kinase pathway. Overexpression and constitutive activation of PKB/Akt leads to human prostate, breast and ovarian carcinomas. A series of 69 PKB/Akt inhibitors were examined to explore their binding modes using FlexX, and three-dimensional quantitative structure–activity relationship (3D-QSAR) studies based on comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed to provide structural insights into these compounds. CoMFA produced statistically significant results, with cross-validated q ² and non-cross validated correlation r ² coefficients of 0.53 and 0.95, respectively. For CoMSIA, steric, hydrophobic and hydrogen bond acceptor fields jointly yielded ‘leave one out’ q ²  = 0.51 and r ²  = 0.84. The predictive power of CoMFA and CoMSIA was determined using a test set of 13 molecules, which gave correlation coefficients, of 0.58 and 0.62, respectively. Molecular docking revealed that the binding modes of these molecules in the ATP binding sites of the Akt kinase domain were very similar to those of the co-crystallized ligand. The information obtained from 3D contour maps will allow the design of more potent and selective Akt kinase inhibitors.