Molecular Modeling Research Articles

Unveiling the multifaceted interactions of antitumor drug mitoxantrone with ct-DNA through biophysical and in silico studies

Mitoxantrone, an anthraquinone derivative, is a widely used anticancer drug with its well-known ability to engage in complex interactions with DNA. Although known for its intercalating ability, the enigma surrounding its binding modes with DNA persists. The existing corpus of literature primarily focuses on mitoxantrone-DNA interactions with short DNA sequences, thereby yielding insights into its interactive nature is limited to this specific sequence. This study aims to elucidate the diverse modes with which mitoxantrone interacts with calf thymus DNA using a combination of spectroscopy, calorimetry and in silico studies. The findings from spectroscopic, calorimetric and molecular dynamic results in correlation with existing literature, unveil a fascinating narrative: mitoxantrone intercalates at lower concentrations but promotes condensation at higher concentrations. Although intercalation with side chains positioned in the minor/major groove is the major binding mode in GC-rich sequences, molecular modelling studies hint at an alternative binding mode in AT-rich sequences where it exclusively displays pure electrostatic interaction. These findings underscore the pivotal role of both drug structure and base sequence in dictating binding mode and affinity. Such insights not only deepen the understanding of structure-activity relationships but also hold promise for guiding future drug design strategies.

In vitro and in silico therapeutic properties of Artepillin C and Aromadendrin as collagenase and elastase inhibitors and investigation of anti-Ovarian cancer effects and antioxidant potential

In this investigation, the enzymes collagenase and elastase were inhibited by artepillin.C and aromadendrin molecules with excellent to good IC50 values of 16.65, and 0.79 μM for artepillin.C and 7.31, 19.38, and 10.56 μM for aromadendrin. Using the molecular modeling study, the chemical activity of these compounds against the enzymes, collagenase, and elastase were evaluated. The anti-cancer properties of the compounds were evaluated using the following cell lines: NIH: OVCAR-3, ES-2, UACC-1598, Hs 832(C).T [Hs832.Tc], TOV-21G, UWB1.289. The DPPH (1,1-diphenyl-2-pricrylhydrazyl) free radical scavenging assay was used to measure antioxidant activity, and the spectrophotometric method was used in this work. The chemical activities of artepillin.C and aromadendrin against collagenase and elastase were investigated utilizing the molecular docking study. The anti-cancer activities of the compounds were evaluated against NIH: OVCAR-3, ES-2, UACC-1598, Hs 832(C).T [Hs832.Tc], TOV-21G, UWB1.289 cell lines. Also, some cell lines had best results for aromadendrin like NIH: OVCAR-3, ES-2, UACC-1598, Hs 832(C).T [Hs832.Tc], TOV-21G, UWB1.289 (10.54 ± 0.94, 22.11±2.52, 31.85 ± 4.73, 8.14± 1.52, 17.94 ± 1.88, and 24.31 ± 2.64 μM). The chemical activities of artepillin.C and aromadendrin against some of the expressed surface receptor proteins (folate receptor, CD44, EGFR, Formyl Peptide Receptor–Like 1, M2 muscarinic receptor, and estrogen receptors) in the mentioned cell lines were assessed using the molecular docking calculations. The outcomes provided information on potential interactions and their atomic-level properties. According to the docking scores, the compounds show a high affinity for binding to proteins and enzymes. Furthermore, these substances made good contact with the receptors and enzymes. As a result, these substances may have the ability to suppress cancer cells and enzymes.

Eco-friendly Synthesis of Indole Conjugated Chromeno[d]Pyrimidines as Anti-cancer Agents and their Molecular Modelling Studies

Introduction: Many medicinally active new chemical entities depend on indole conjugated chromeno[d]pyrimidine derivatives as a building block. The synthesis of 4-(1H-indol-3-yl)-3,4- dihydro-1H-chromeno[4,3-d]pyrimidine-2,5-dione 4 were achieved in the current study by treating 4- hydroxy-2H-chromen-2-one 1, indole aldehydes 2, and urea/thiourea 3 in the presence of L-proline. Methods: By adopting the above protocol, we were able to synthesize eight compounds, i.e. 4-(1Hindol- 3-yl)-3,4-dihydro-1H-chromeno[4,3-d]pyrimidine-2,5-diones (4a-4h), in the presence of Lproline as a catalyst in ethanol as solvent for 2-3 hours at 70-75°C with decent yields of 80-85%, and their structures were ascertained by various spectral techniques. They were further screened for their potentiality to inhibit cancer growth in HepG2 and MDA-MD-231 cells. Results: The scope of the synthesis of biological relevant Indole conjugated Chromeno[ d]Pyrimidines by three-component reaction (MCRs) process was investigated. The most optimised conditions obtained were 0.3 eq of L-proline for 2 hours at 70-75°C which gave the best yield (85%). The few advantages of this newly developed method are excellent yields, no metal catalyst, less toxic solvents, simple workup no chromatographic column purifications. On further screening for their anticancer activities, out of all, the compound 4b displayed noteworthy cytotoxicity with IC50 values of 8.1 and 9.2 μM against HepG2 and MDA-MD-231, respectively. Additionally, in silico studies also supported that compound 4b had favourable binding energy (-7.8 kcal/mol) when compared to the co-crystal ligand (LS5) in inhibiting the human cyclin-dependent kinase 2 (CDK2) protein. Conclusion: In conclusion, we have developed a simple, convenient, and efficient method for the synthesis of structurally diverse indole conjugated chromeno[d]pyrimidine analogues in the presence of L-proline as catalyst in ethanol as solvent with good yields. Further, the in vitro cytotoxic studies against HepG2 and MDA-MD-231 cells demonstrated that the synthesized compounds had good to reasonable activity, except for compound 4d.

Structural parameters and molecular model of Shendong subbituminous coal

Coal has a highly complex chemical structure, similar to polymers, coal is a macromolecular structure composed of a large number of “similar compounds”, which is called the basic structural unit. Understanding coal structure is the basis of its transformation and utilization. Shendong (SD) coal was analyzed by FTIR, XRD, XPS, and NMR. The results show that SD coal normalized structure formula is C100H68.5O35.7N1.2S0.2 and the average number of aromatic rings is 1.98. –CH2— content accounts for about 82% in aliphatic C–H region, and the ratio of ether bond C–O, aromatic ether C–O and CO is about 2:1:11 in oxygen-containing functional group region. The d002, LC, La and NC of SD coal microcrystalline structure parameters are 0.1832 nm, 1.4688 nm, 2.0852 nm and 9.017, respectively. Aromatic carbon and aliphatic carbon ratios of SD coal are 55.67% and 29.97%, aromatic cluster size and average methylene chain length are 0.224 and 1.817. Based on these structural parameters, molecular model of SD coal was constructed with 13C SSNMR experimental spectra as a reference. The model was constructed with an atom composition of C214H214O49N2S.

ReaxFF simulations on the transformation pathway of nitrogen elements in the heavy tar under oxy-coal combustion

Heavy tar is a crucial intermediate product during coal combustion. To explore the transformation pathway of N atoms in heavy tar under oxy-coal combustion, a comprehensive molecular model of heavy tar with typical N-containing functional groups was constructed. Different temperatures and chemical equivalence ratios were set for the oxy-coal combustion. The ReaxFF was employed to study various products' distribution and molecular numbers. The reaction network among different precursors and NOx was extracted, and the NO to N2 conversion mechanism was summarized. The results indicated that, like char combustion, the proportion of heavy tar gradually declined, the proportion of light tar and organic gas first rose and then gradually declined, and the proportion of inorganic gas continuously rose during heavy tar combustion. As the temperature increased, the proportion of cyanide precursors decreased, while the proportion of amine precursors and NOx increased. The oxidation of N-containing intermediates became more intense as the O2 content rose, but this oxidation effect was inhibited, and the NOx generation was reduced as the O2 content further increased. NO could bond with NHi, HNO, CN, and activate NO, decomposing to produce N2O, and N2O reacted with H radical to produce N2.

Calculating the surface energies of crystals on a face-specific and whole particle basis: Case study of the α- and β-polymorphic forms of L-glutamic acid

Molecular-scale modelling for predicting surface energies on a face-specific and whole particle basis is applied to all the crystallographically-independent surfaces of L-glutamic acid forms. The predicted data is found to be in good general agreement with measured surface energies using inverse gas chromatography and Washburn capillary rise techniques with the former revealing higher values compared to the prediction, perhaps consistent with the polar (zwitterionic) nature of this material. This fusion of experimental and computational data provides a high-fidelity definition of the face-by-face breakdown of the energetic anisotropy of the crystals. There is increasing industrial interest in defining the potential impact of whole particle properties on the performance of formulated drug product and their manufacturability especially as the community accelerates the molecule to medicine journey. The overall molecular modelling approach highlights its application in designing ingredients for optimising face-specific particle surface energies for product formulatability particularly in early phase process development.

P05-35 Molecular modelling study on CYP2C19 mediated biotransformation of organophosphorothioate pesticides: insights on a possible mutational landscape

P05-35 Molecular modelling study on CYP2C19 mediated biotransformation of organophosphorothioate pesticides: insights on a possible mutational landscape

Jack bean urease inhibition by different root fractions of Cleome gynandra L – Kinetic mechanism and computational molecular modelling

Natural products with urease inhibiting potentialities would be valuable for enhancing nitrogen fertilizer formulations and developing new therapeutics against infectious diseases. Main focus of this research was to assess the inhibitory impact of various parts of Cleome gynandra (Cleomaceae) on jack bean urease activity, identify the responsible compounds, and ascertain their mode of enzyme inhibition and interactions with urease enzyme. Urease inhibitory potentiality of different plant parts of C. gynandra was determined using the phenol-hypochlorite method and mode of enzyme inhibition by Lineweaver-Burk kinetic analysis. LC-HRMS was carried out to identify the compounds of the active fractions. Molecular docking and simulations were executed to find out the binding affinity and interaction pattern of the isolated compounds at the active site of urease enzyme and to verify stability of protein-inhibitor complexes. The root of C. gynandra exhibited highest urease inhibitory potentiality with IC50 value of 1.529 mg/ml compared with leaf and stem. Among the different root fractions, water fraction revealed maximum anti-urease activity with IC50 values of 1.477 mg/ml followed by methanol (1.655 mg/ml) and acetone fractions (1.955 mg/ml). Inhibition kinetics indicated that these fractions were strong inhibitors of urease and exhibited a non-competitive mode of inhibition with Ki values of 184.911 µg/ml, 147.34 µg/ml, and 233.75 µg/ml respectively at 1000 mg/L concentration. LC-HRMS analysis confirmed the occurrence of glucocapparin, fluticasone propionate and lauryl hydrogen sulfate etc. in water fraction. Molecular modelling and simulation study suggested strong and stable interactions between the specified compounds of water fraction and active site of urease. Hence, the water fraction of C. gynandra roots represent a valuable source of natural urease inhibitors, for possible therapeutic applications and sustainable agricultural practices.

Synthesis and evaluation of lipoic acid – donepezil hybrids for Alzheimer’s disease using a straightforward strategy

Alzheimer’s disease is associated with a progressive loss of neurons and synaptic connections in the cholinergic system. Oxidative stress contributes to neuronal damages and to the development of amyloid plaques and neurofibrillary tangles. Therefore, antioxidants have been widely studied to mitigate the progression of Alzheimer’s disease, and among these, lipoic acid has demonstrated a neuroprotective effect. Here, we present the synthesis, the molecular modelling, and the evaluation of lipoic acid–donepezil hybrids based on O-desmethyldonepezil. As compounds 5 and 6 display a high inhibition of acetylcholinesterase (IC50 = 7.6 nM and 9.1 nM, respectively), selective against butyrylcholinesterase, and a notable neuroprotective effect, slightly better than that of lipoic acid, the present study suggests that O-desmethyldonepezil could serve as a platform for the straightforward design of donepezil hybrids.

Exploring pathogenic SNPs and estrogen receptor alpha interactions in breast cancer: An in silico approach

The estrogen receptor 1 gene (ESR1) plays a crucial role in breast and mammary development in humans. Alterations such as gene amplification, genomic rearrangements, and missense mutations in the ESR1 gene are reported to increase the risk of breast cancer in humans. The purpose of this study is to analyze the missense mutations and molecular modeling of ESR1, focusing on the pathogenic SNP H516N, for a better understanding of disease risk and future benefits for therapeutic benefits. This SNP was selected based on its location in the binding pocket of ESR1 and its predicted impact on drug binding. The in silico analysis was performed by applying various computational approaches to identify highly pathogenic SNPs in the binding pocket of ESR1. The effect of the SNP was explored through docking and intra-molecular interaction studies. All SNPs in ESR1 were identified followed by the identification of the highly pathogenic variant located in the binding pocket of ESR1. The mutant model of the pathogenic SNP H516N was generated, and hydroxytamoxifen was docked with the wild-type and the mutant model. The mutant model lost the formation of stable hydrogen bonds with the active site residues and hydroxytamoxifen, which may result in reduced binding affinity and therefore, will predict the patient's response to estrogenic inhibitors.

Applying Molecular Modeling to the Design of Innovative, Non-Symmetrical CXCR4 Inhibitors with Potent Anticancer Activity.

The identification of new compounds with potential activity against CXC chemokine receptor type 4 (CXCR4) has been broadly studied, implying several chemical families, particularly AMD3100 derivatives. Molecular modeling has played a pivotal role in the identification of new active compounds. But, has its golden age ended? A virtual library of 450,000 tetraamines of general structure 8 was constructed by using five spacers and 300 diamines, which were obtained from the corresponding commercially available cyclic amines. Diversity selection was performed to guide the virtual screening of the former database and to select the most representative set of compounds. Molecular docking on the CXCR4 crystal structure allowed us to rank the selection and identify those candidate molecules with potential antitumor activity against diffuse large B-cell lymphoma (DLBCL). Among them, compound A{17,18} stood out for being a non-symmetrical structure, synthetically feasible, and with promising activity against DLBCL in in vitro experiments. The focused study of symmetrical-related compounds allowed us to identify potential pre-hits (IC50~20 µM), evidencing that molecular design is still relevant in the development of new CXCR4 inhibitor candidates.

Investigation of biological activity of oxindole semicarbazones based copper (II) complexes: Synthesis, antimicrobial activities and molecular modelling

Copper (II) acetate reacted with 2-oxindole semicarbazone (2-Hoxsc, H1L), 3-methyl 2-oxindole semicarbazone (3-MeHoxsc, H2L) and 6-Chloro-2-oxindole semicarbazone (6-ClHoxsc, H3L) in 1:2 (M:L) molar ratio to form complexes of general formula, [Cu(L2)] (1L, 1; 2L 2; 3L 3. Stoichiometric ratio of complexes was established using UV–Vis spectroscopy. All the complexes were characterised by the CHN analysis, IR, ESR spectroscopy and Mass spectrometry. From the ESR spectrum, g values obtained (g‖ = 2.20; g⊥ = 2.05) for complex 2 confirms axial symmetry for this complex, whereas a broad isotropic signal in 1 and 3 (giso = 2.060, 1; 2.057, 3) indicates extensive exchange coupling. All the synthesized compounds (ligands and complexes) complexes were examined for their anti-tubercular activity against M. tuberculosis H37RV strain. Compounds were also tested for their anti-bacterial (B. subtilis, K. pneumonia) and antifungal (C. auris, C. albicans) activities. Biological investigations revealed that the antimicrobial activities (anti-TB, antibacterial and antifungal) of ligands get improved on complexation with Cu (II) due to formation of chelate ring, which can make the ligand a more powerful biological agent. Complex 3 has shown excellent anti-TB (MIC = 1.6 g/ml) and antibacterial (ZOI = 26 mm at 5 mg/mL) activities. Strong binding of complex 3 was observed (Kb = 24.22 × 105 M−1) with Human Serum Albumin (HSA) using fluorescence spectroscopy. Molecular modelling of complex 3 was also done with the active site of amino acid of M. tuberculosis enoyl reductase. The minimal binding energy of −10.1 kcal/mol indicated significant intermolecular interaction between M. tuberculosis enoyl reductase and complex 3 and is in well agreement with experimental data.

A molecular phylogeny of the Petaluridae (Odonata: Anisoptera): A 160-Million-Year-Old story of drift and extinction

Petaluridae (Odonata: Anisoptera) is a relict dragonfly family, having diverged from its sister family in the Jurassic, of eleven species that are notable among odonates (dragonflies and damselflies) for their exclusive use of fen and bog habitats, their burrowing behavior as nymphs, large body size as adults, and extended lifespans. To date, several nodes within this family remain unresolved, limiting the study of the evolution of this peculiar family. Using an anchored hybrid enrichment dataset of over 900 loci we reconstructed the species tree of Petaluridae. To estimate the temporal origin of the genera within this family, we used a set of well-vetted fossils and a relaxed molecular clock model in a divergence time estimation analysis. We estimate that Petaluridae originated in the early Cretaceous and confirm the existence of monophyletic Gondwanan and Laurasian clades within the family. Our relaxed molecular clock analysis estimated that these clades diverged from their MRCA approximately 160 mya. Extant lineages within this family were identified to have persisted from 6 (Uropetala) to 120 million years (Phenes). Our biogeographical analyses focusing on a set of key regions suggest that divergence within Petaluridae is largely correlated with continental drift, the exposure of land bridges, and the development of mountain ranges. Our results support the hypothesis that species within Petaluridae have persisted for tens of millions of years, with little fossil evidence to suggest widespread extinction in the family, despite optimal conditions for the fossilization of nymphs. Petaluridae appear to be a rare example of habitat specialists that have persisted for tens of millions of years.

Hydrogen bonding patterns and cooperativity in polyproline II helical bundles

Hydrogen bond cooperativity (HBC) plays an important role in stabilizing protein assemblies built by α-helices and β-sheets, the most common secondary structures. However, whether HBC exists in other types of protein secondary structures such as polyproline II (PPII) helices remains unexplored. This is intriguing, since PPII systems as assembling blocks are continuously emerging across multiple fields. Here, using a combination of computational chemistry tools and molecular modeling corroborated by experimental observables, we characterize the distinct H-bonding patterns present in PPII helical bundles and establish that HBC stabilizes intermolecular PPII helices as seen in other protein assemblies such as amyloid fibrils. In addition to cooperative interactions in canonical CO···HN H-bonds, we show that analogous interactions in non-canonical CO···HαCα H-bonds are relevant in Gly-rich PPII bundles, thus compensating for the inability of glycine residues to create hydrophobic cores. Our results provide a mechanistic explanation for the assembly of these bundles.

Study on the Factors Affecting the Self-Healing Performance of Graphene-Modified Asphalt Based on Molecular Dynamics Simulation.

To comprehensively understand the impact of various environmental factors on the self-healing process of graphene-modified asphalt, this study employs molecular dynamics simulation methods to investigate the effects of aging degree (unaged, short-term aged, long-term aged), asphalt type (base asphalt, graphene-modified asphalt), healing temperature (20 °C, 25 °C, 30 °C), and damage degree (5 Å, 10 Å, 15 Å) on the self-healing performance of asphalt. The validity of the established asphalt molecular models was verified based on four physical quantities: density, radial distribution function analysis, glass transition temperature, and cohesive energy density. The simulated healing time for the asphalt crack model was set to 200 ps. The following conclusions were drawn based on the changes in density, mean square displacement, and diffusion coefficient during the simulated healing process under different influencing factors: Dehydrogenation and oxidation of asphalt molecules during the aging process hinder molecular migration within the asphalt crack model, resulting in poorer self-healing performance. As the service life increases, the decline in the healing performance of graphene-modified asphalt is slower than that of base asphalt, indicating that graphene-modified asphalt has stronger anti-aging properties. When the vacuum layer in the asphalt crack model is small, the changes in the diffusion coefficient are less pronounced. As the crack width increases, the influence of various factors on the diffusion coefficient of the asphalt crack model becomes more significant. When the crack width is large, the self-healing effect of asphalt is more dependent on these influencing factors. Damage degree and oxidative aging have a more significant impact on the healing ability of graphene-modified asphalt than healing temperature.

Synthesis of some benzothiazole-piperazine derivatives, investigation by in vitro and molecular modelling for hMAO inhibitory activities

Synthesis of some benzothiazole-piperazine derivatives, investigation by in vitro and molecular modelling for hMAO inhibitory activities

Development of ketobenzothiazole-based peptidomimetic TMPRSS13 inhibitors with low nanomolar potency.

TMPRSS13, a member of the Type II Transmembrane Serine Proteases (TTSP) family, is involved in cancer progression and in cell entry of respiratory viruses. To date, no inhibitors have been specifically developed toward this protease. In this study, a chemical library of 65 ketobenzothiazole-based peptidomimetic molecules was screened against a proteolytically active form of recombinant TMPRSS13 to identify novel inhibitors. Following an initial round of screening, subsequent synthesis of additional derivatives supported by molecular modelling, uncovered important molecular determinants involved in TMPRSS13 inhibition. One inhibitor, N-0430, achieved low nanomolar affinity towards TMPRSS13 activity in a cellular context. Using a SARS-CoV-2 pseudovirus cell entry model, we further show the ability of N-0430 to block TMPRSS13-dependent entry of the pseudovirus. The identified peptidomimetic inhibitors and the molecular insights of their potency gained from this study will aid in the development of specific TMPRSS13 inhibitors.

Comparison between imidacloprid effects on AChE and nAChRα1 in target Aphis craccivora and non-target Apis mellifera: experimental and theoretical approaches

BackgroundNeonicotinoids are widespread insecticides because of their potent effects against aphids and other piercing-sucking insects in addition to having high selectivity toward insects rather than vertebrates. However, they affect severely some non-target insects, mainly honeybee in a phenomenon called colony collapse disorder (CCD).ResultsEffects of imidacloprid (IMI), most used neonicotinoids, on aphid acetylcholinesterase (AChE), in vivo and in vitro were examined; besides, molecular modeling was used to investigate similarities and differences of AChE and nicotinic acetylcholine receptors α1-subunit (nAChRα1) in aphids, target insect, and honeybees, non-target insect. Results showed that aphid AChE was inhibited in vitro, with IC50 108.6 mg/L but not affected in vivo while the mortality was concentration-dependent with high toxicity (LC50 9.50 mg/L); in addition, aphid AChE was more inhibited, in vitro, but with much less effects, in vivo, than that of honeybees. These results indicate that AChE is not the main cause of the observed mortality, but it still has a role in insect resistance system with different responses in both insects. Molecular modeling showed high similarity in primary and secondary structures of AChE indicated by high identity (67%) and low gaps (1%); besides, the same template for both enzymes was auto-selected for homology. In addition, similar positions of the triad amino acids were found in AChE of both insects indicating high similarity. Conversely, the similarity in nAChRα1 in both insects is lower (50% identity and 9% gaps). These gaps (50 amino acids) are found in the intracellular large loop between TM3 and TM4 and account for the observed differences in the nAChRα1 binding sites of in both insects.ConclusionThese observed variations in nAChRα1 structures and binding sites in different insect species can be used as good bases in designing new neonicotinoids that express high effects on target insects with better selectivity to minimize adverse effects on non-target organisms.Graphical

Conformational Space Profiling Enhances Generic Molecular Representation for AI-Powered Ligand-Based Drug Discovery.

The molecular representation model is a neural network that converts molecular representations (SMILES, Graph) into feature vectors, and is an essential module applied across a wide range of artificial intelligence-driven drug discovery scenarios. However, current molecular representation models rarely consider the three-dimensional conformational space of molecules, losing sight of the dynamic nature of small molecules as well as the essence of molecular conformational space that covers the heterogeneity of molecule properties, such as the multi-target mechanism of action, recognition of different biomolecules, dynamics in cytoplasm and membrane. In this study, a new model named GeminiMol is proposed to incorporate conformational space profiles into molecular representation learning, which extracts the feature of capturing the complicated interplay between the molecular structure and the conformational space. Although GeminiMol is pre-trained on a relatively small-scale molecular dataset (39290 molecules), it shows balanced and superior performance not only on 67 molecular properties predictions but also on 73 cellular activity predictions and 171 zero-shot tasks (including virtual screening and target identification). By capturing the molecular conformational space profile, the strategy paves the way for rapid exploration of chemical space and facilitates changing paradigms for drug design.

Higher levels of AKT-interacting protein in the frontal pole from people with schizophrenia are limited to a sub-group who have a marked deficit in cortical muscarinic M1 receptors

We are studying the molecular pathology of a sub-group within schizophrenia (∼ 25 %: termed Muscarinic Receptor Deficit subgroup of Schizophrenia (MRDS)) who can be separated because they have very low levels of cortical muscarinic M1 receptors (CHRM1). Based on our transcriptomic data from Brodmann's area ((BA) 9, 10 and 33 (controls, schizophrenia and mood disorders) and the cortex of the CHRM1−/− mouse (a molecular model of aberrant CHRM1 signaling), we predicted levels of AKT interacting protein (AKTIP), but not tubulin alpha 1b (TUBA1B) or AKT serine/threonine kinase 1 (AKT1) and pyruvate dehydrogenase kinase 1 (PDK1) (two AKTIP-functionally associated proteins), would be changed in MRDS. Hence, we used Western blotting to measure AKTIP (BA 10: controls, schizophrenia and mood disorders; BA 9: controls and schizophrenia) plus TUBA1B, AKT1 and PDK1 (BA 10: controls and schizophrenia) proteins. The only significant change with diagnosis was higher levels of AKTIP protein in BA 10 (Cohen's d = 0.73; p = 0.02) in schizophrenia compared to controls due to higher levels of AKTIP only in people with MRDS (Cohen's d = 0.80; p = 0.03). As AKTIP is involved in AKT1 signaling, our data suggests that signaling pathway is particularly disturbed in BA 10 in MRDS.