Pharmaceutical Research (v.26, #9)

Drug transporters are recognized as key players in the processes of drug absorption, distribution, metabolism, and elimination. The localization of uptake and efflux transporters in organs responsible for drug biotransformation and excretion gives transporter proteins a unique gatekeeper function in controlling drug access to metabolizing enzymes and excretory pathways. This review seeks to discuss the influence intestinal and hepatic drug transporters have on pharmacokinetic parameters, including bioavailability, exposure, clearance, volume of distribution, and half-life, for orally dosed drugs. This review also describes in detail the Biopharmaceutics Drug Disposition Classification System (BDDCS) and explains how many of the effects drug transporters exert on oral drug pharmacokinetic parameters can be predicted by this classification scheme.
Keywords: BDDCS; drug transporters; hepatic; intestinal; transporter/enzyme interplay

Inner Blood-Retinal Barrier Transporters: Role of Retinal Drug Delivery by Ken-ichi Hosoya; Masanori Tachikawa (2055-2065).
The inner blood-retinal barrier (inner BRB) forms complex tight junctions of retinal capillary endothelial cells to prevent the free diffusion of substances between the circulating blood and the neural retina. Thus, understanding of the inner BRB transport mechanisms could provide a basis for the development of strategies for drug delivery to the retina. Recent progress in inner BRB research has revealed that retinal endothelial cells express a variety of unique transporters which play a role in the influx transport of essential molecules and the efflux transport of xenobiotics. In this review we focus on the transport mechanism at the inner BRB in relation to its importance in influencing the inner BRB permeability of drugs.
Keywords: carrier-mediated transport; efflux transport; influx transport; inner blood-retinal barrier; retinal capillary endothelial cells; transporter

Anti-Cancer, Anti-Diabetic and Other Pharmacologic and Biological Activities of Penta-Galloyl-Glucose by Jinhui Zhang; Li Li; Sung-Hoon Kim; Ann E. Hagerman; Junxuan Lü (2066-2080).
1, 2, 3, 4, 6-penta-O-galloyl-β-D-glucose (PGG) is a polyphenolic compound highly enriched in a number of medicinal herbals. Several in vitro and a handful of in vivo studies have shown that PGG exhibits multiple biological activities which implicate a great potential for PGG in the therapy and prevention of several major diseases including cancer and diabetes. Chemically and functionally, PGG appears to be distinct from its constituent gallic acid or tea polyphenols. For anti-cancer activity, three published in vivo preclinical cancer model studies with PGG support promising efficacy to selectively inhibit malignancy without host toxicity. Potential mechanisms include anti-angiogenesis; anti-proliferative actions through inhibition of DNA replicative synthesis, S-phase arrest, and G1 arrest; induction of apoptosis; anti-inflammation; and anti-oxidation. Putative molecular targets include p53, Stat3, Cox-2, VEGFR1, AP-1, SP-1, Nrf-2, and MMP-9. For anti-diabetic activity, PGG and analogues appear to improve glucose uptake. However, very little is known about the absorption, pharmacokinetics, and metabolism of PGG, or its toxicity profile. The lack of a large quantity of highly pure PGG has been a bottleneck limiting in vivo validation of cancer preventive and therapeutic efficacies in clinically relevant models.
Keywords: anti-angiogenesis; anti-cancer; anti-diabetes; gallotannin; polyphenols

Micellar Delivery of Bicalutamide and Embelin for Treating Prostate Cancer by Michael Danquah; Feng Li; Charles B. Duke III; Duane D. Miller; Ram I. Mahato (2081-2092).
To examine the effect of bicalutamide and embelin on the growth of prostate cancer cells in vitro and in vivo Cell viability was determined by MTT assay. Micelles were fabricated with polyethylene glycol-b-polylactic acid (PEG-PLA) copolymer and characterized in terms of particle size, micellar solubilization and drug loading, followed by evaluation in nude mice bearing LNCaP xenografts.Embelin induced caspase 3 and 9 activation in LNCaP and C4–2 cells by decreasing XIAP expression and was more potent than bicalutamide in killing prostate tumor cells irrespective of their androgen status. As analyzed by isobologram analysis the combination of bicalutamide and embelin was synergistic for C4–2 but additive and slightly antagonistic for LNCaP cells. Micellar formulation resulted in at least 60-fold increase in the aqueous solubility of bicalutamide and embelin. Tumor growth was effectively regressed upon treatment with bicalutamide, but the extent of tumor regression was significantly higher when bicalutamide was formulated in micelles. However, tumor response to bicalutamide stopped after prolonged treatment and began to grow. Sequential treatment with XIAP inhibitor embelin resulted in regression of these hormone refractory tumors.Combined treatment with bicalutamide and embelin may be an effective strategy for treating hormone refractory prostate cancer.
Keywords: androgen; bicalutamide; embelin; micelles; prostate cancer

Powder Dissolution Method for Estimating Rotating Disk Intrinsic Dissolution Rates of Low Solubility Drugs by Konstantin Tsinman; Alex Avdeef; Oksana Tsinman; Dmytro Voloboy (2093-2100).
The objective was to investigate the applicability and limitations of a novel approach for measuring intrinsic dissolution rates (IDR) of very small quantities of compounds introduced as powders to buffered solutions and comparing these results to disk IDR obtained using the traditional Wood’s apparatus.The powder dissolution profiles of 13 model drugs were determined at 37°C in USP buffers at pH 1.2, 4.5, and 6.8, stirred at 100 RPM. As little as 0.06 mg of drug were added to 1 mL buffer media. Drug concentration was measured by an in situ fiber optic UV method. The results were converted to rotating disk IDR values by a novel mathematical procedure.The comparison of the powder-based IDR values to those obtained by traditional Wood’s apparatus indicated r2 = 0.97 (n = 26).The results demonstrate that using potentially 10,000-fold less drug material does not sacrifice the quality of the measurement, and lends support to an earlier study that the disk IDR measurement may possibly serve as a surrogate for the BCS solubility classification.
Keywords: Biopharmaceutics classification system; Low solubility; Powder IDR; Rotating disk intrinsic dissolution rate; Wood’s apparatus

To develop paclitaxel-delivering PLGA microspheres entrapped in a gel matrix with sustained drug release properties and implantability advantages for local glioma chemotherapy.Paclitaxel-loaded PLGA microspheres were fabricated using electrohydrodynamic atomization and entrapped by electrospray and gelation. The physicochemical characterizations were performed using scanning electron microscopy and differential scanning calorimetry. The influence of various parameters on the disintegration time was investigated. In vitro release of paclitaxel was quantified using high performance liquid chromatography. Cytotoxicity of the formulations was assessed by the quantification of IC50 and caspase-3 activity against C6 glioma cells in vitro. The formulations were tested against a subcutaneous C6 glioma tumour in mice.Highly monodisperse gel beads containing a uniform microsphere distribution were obtained. Gelation using Ca2+ ions ensured entrapment of microspheres with high loading efficiency. With an increase in the gelation time, gelling bath concentration and decrease in microsphere loading, it was more difficult to disintegrate the beads and release the microspheres. The formulations demonstrated sustained drug release for more than 60 days at a near-constant rate and a low initial burst. Cell culture studies proved the cytotoxicity against C6 glioma and improved performance in comparison to Taxol®. The formulations could reduce subcutaneous tumour volume to a greater extent compared to Taxol® and the control.Paclitaxel-loaded PLGA microspheres entrapped in an alginate gel matrix could be potential local chemotherapy implants to treat malignant glioma with critical advantages of implantability and sustained drug release with low initial burst.
Keywords: chemotherapy; electrohydrodynamic atomization; glioma; hydrogel; microspheres; PLGA-paclitaxel

To elucidate the key parameters affecting solute transport from semi-interpenetrating networks (sIPNs) comprised of poly(ethylene glycol) diacrylate (PEGdA) and gelatin that are partially crosslinked, water-swellable and biodegradable. Effects of material compositions, solute size, solubility, and loading density have been investigated.sIPNs of following gelatin/PEGdA weight-to-weight ratios were prepared: 10:15, 10:20, 10:30, 15:15, 20:15. Five model solutes of different physicochemical properties were selected, i.e. silver sulfadiazine (AgSD), bupivacaine hydrochloride (Bup), sulfadiazine sodium (NaSD), keratinocyte growth factor (KGF), and bovine serum albumin conjugated with fluorescein isothiocyanate (BSA-FITC). Release studies were performed and the results were analyzed using three hydrogel based common theories (free volume, hydrodynamic and obstruction).The release kinetics of model solutes was influenced by each factor under investigation. Specifically, the initial release rates and intra-gel diffusivity decreased with increasing PEGdA content or increasing solute molecular weight. However, the initial release rate and intra-gel diffusivity increased with increasing gelatin content or increasing solute water solubility, which contradicted with the classical hydrogel based solute transport theories, i.e. increasing polymer volume leads to decreased solute diffusivity within the gel.This analysis provides structure-functional information of the sIPN as a potential therapeutic delivery matrix.
Keywords: diffusion; gelatin; poly(ethylene glycol) diacrylate; semi-interpenetrating network

Lactoferrin Conjugated with 40-kDa Branched Poly(ethylene Glycol) Has an Improved Circulating Half-Life by Yasuhiro Nojima; Yosuke Suzuki; Kazuhiro Yoshida; Fumiko Abe; Tuneo Shiga; Takashi Takeuchi; Akihiko Sugiyama; Hirohiko Shimizu; Atsushi Sato (2125-2132).
We developed a lactoferrin conjugate by modifying bovine lactoferrin (bLF) with a 40-kDa branched poly(ethylene glycol) (PEG) molecule (designated 40 k-PEG-bLf), and we evaluated its in vitro activities and pharmacokinetic properties.We prepared 40k-PEG-bLf by amino conjugation with N-hydroxysuccinimide-activated PEG. This conjugate was purified by cation exchange chromatography and its in vitro biological activities, such as iron binding, anti-inflammatory effects, and resistance to proteolytic enzymes were investigated. In vivo pharmacokinetics analyses, were also performed to examine the rate of clearance from the plasma in rats.The 40k-PEG-bLf conjugate was fully active in iron binding and exhibited 97.1 ± 5.5% (mean ± S.E., n = 6) of the original anti-inflammatory activity. The in vitro peptic susceptibility of 40 k-PEG-bLf revealed that the proteolytic half-life increased at least 6-fold that of unmodified LF. This PEGylated conjugate demonstrated a plasma half-life that was 8.7-fold longer than that of the unmodified bLF in rats.The 40k-PEG-bLf exhibited improved in vitro bioactivity and stability and enhanced pharmacokinetic properties as compared to those of the unmodified bLF and the 20 k-PEG-bLf conjugate, which was recently developed by PEGylation of bLF with a 20-kDa branched PEG [Nojima Y. et al. Bioconjugate Chem. 19:2253–2259 (2008)].
Keywords: bioactivity; branched PEG; lactoferrin; pharmacokinetics; stability

Gallic acid, a natural agent present in a wide-range of fruits and vegetables, has been of potential interest as an anti-cancer agent; herein, we evaluated its efficacy in androgen-independent DU145 and androgen-dependent-22Rv1 human prostate cancer (PCa) cells.Cell viability was determined by MTT and apoptosis by Annexin V-PI assays. In vivo anti-cancer efficacy was assessed by DU145 and 22Rv1 xenograft growth in nude mice given normal drinking water or one supplemented with 0.3% or 1% (w/v) gallic acid. PCNA, TUNEL and CD31 immunostaining was performed in tumor tissues for in vivo anti-proliferative, apoptotic and anti-angiogenic effects of gallic acid.Gallic acid decreased cell viability in a dose-dependent manner in both DU145 and 22Rv1 cells largely via apoptosis induction. In tumor studies, gallic acid feeding inhibited the growth of DU145 and 22Rv1 PCa xenografts in nude mice. Immunohistochemical analysis revealed significant inhibition of tumor cell proliferation, induction of apoptosis, and reduction of microvessel density in tumor xenografts from gallic acid-fed mice as compared to controls in both DU145 and 22Rv1 models.Taken together, our findings show the anti-PCa efficacy of gallic acid and provide a rationale for additional studies with this naturally-occurring agent for its efficacy against PCa.
Keywords: apoptosis; cell proliferation; chemoprevention; gallic acid; prostate cancer

Characterization of the Contents of Ascending Colon to Which Drugs are Exposed After Oral Administration to Healthy Adults by Amalia Diakidou; Maria Vertzoni; Konstantinos Goumas; Erik Söderlind; Bertil Abrahamsson; Jennifer Dressman; Christos Reppas (2141-2151).
To characterize the contents of the ascending colon in healthy adults under fasting and fed state conditions, with a view to designing in vitro studies to explain/predict dosage form performance in the lower gut.Twelve healthy adults participated in a two-phase crossover study. In Phase A, subjects were fasted (water allowed) overnight plus 5 h in the morning prior to colonoscopy (fasted state). In Phase B, subjects were fasted overnight, consumed a standard breakfast (960 kcal) in the morning, and were offered a light lunch 4.5 h later. In this phase, colonoscopy was performed 1 h after lunch (fed state). Volume, pH, and buffer capacity of colonic contents were measured immediately upon collection. After ultracentrifugation, the supernatant was further characterized.Free water content, pH, surface tension, and isobutyrate levels were lower in fed than in fasted subjects. On the other hand, buffer capacity, osmolality, acetate, butyrate, cholate, and chenodeoxycholate levels were higher in fed subjects. Carbohydrate content; protein content; and levels of long chain fatty acids, phosphatidylcholine, and cholesterol were not affected significantly by prandial state.Composition of fluids in the ascending colon is affected by feeding. This may affect the performance of products designed to deliver drug to the colon.
Keywords: ascending colon; charged aerosol detector (CAD); fasted state; fed state; lumenal composition

Fabrication of a Novel Core-Shell Gene Delivery System Based on a Brush-Like Polycation of α, β–Poly (L-Aspartate-Graft-PEI) by Jia-Hui Yu; Ji-Shan Quan; Jung-Taek Kwon; Cheng-Xiong Xu; Bo Sun; Hu-Lin Jiang; Jae-Woon Nah; Eun-Mi Kim; Hwan-Jeong Jeong; Myung-Haing Cho; Chong-Su Cho (2152-2163).
A novel core-shell gene delivery system was fabricated in order to improve its gene transfection efficiency, particularly in the presence of serum.α, β–poly (L-aspartate-graft-PEI) (PAE) was simply synthesized by ring-opening reaction of poly (L-succinimide) with low molecular weight (LMW) linear polyethylenimine (PEI, Mn = 423). PAE/DNA nanoparticles were characterized. Condensation and protection ability of plasmid by PAE were confirmed by agarose gel electrophoresis assay. Cytotoxicity of the polymer and polymer/DNA nanoparticles were measured by MTS assay. Gene transfection efficiencies were evaluated both in vitro and in vivo.Core-shell nanoparticles assembled between DNA and PAE showed positive zeta potential, narrow size distribution, and spherical compact shapes with size below 250 nm when N/P ratio is above 10. Cytotoxicity of PAE was rather lower than that of PEI 25K, while the most efficient gene transfection and serum resistant ability of PAE/DNA complexes were higher than that of PEI 25K. Bafilomycin A1 treatment suggested “proton sponge” mechanism of PAE-mediated gene transfection. PAE/pEGFP-N2 nanoparticles also showed good gene expression in vivo and were dominantly distributed in kidney, liver, spleen and lung after intravenous administration.The results demonstrated the potential use of PAE as an effective gene carrier.
Keywords: core-shell nanoparticles; gene delivery; poly (L-succinimide); polyethylenimine; α, β–Poly (L-aspartate-graft-PEI)

Self-Assembled Hydrophobic Honokiol Loaded MPEG-PCL Diblock Copolymer Micelles by MaLing Gou; XiuLing Zheng; Ke Men; Juan Zhang; BiLan Wang; Lei Lv; XiuHong Wang; YinLan Zhao; Feng Luo; LiJuan Chen; Xia Zhao; YuQuan Wei; ZhiYong Qian (2164-2173).
Honokiol showed potential application in cancer treatment, but its poor water solubility restricts its clinical application greatly. So, we designed a self-assembled monomethoxy poly(ethylene glycol)-poly(ε-caprolactone) (MPEG-PCL) micelle to load honokiol to overcome its poor water solubility.We synthesized MPEG-PCL diblock copolymer that could self-assemble into monodisperse micelles at the particle size of ca.18 nm in water. Honokiol was loaded into MPEG-PCL micelle by direct dissolution method assisted by ultrasound, without any surfactants, organic solvents, and vigorous stirring.The blank MPEG-PCL micelles (100 mg/mL) did not induce any hemolysis in vitro and showed very low toxicity ex vivo and in vivo. Honokiol could be molecularly incorporated into MPEG-PCL micelles at the drug loading of about 20% by direct dissolution method assisted by ultrasound. After loaded into MPEG-PCL micelles, honokiol maintained its molecular structure and anticancer activity in vitro. Honokiol could be sustained released from MPEG-PCL micelles in vitro. The honokiol loaded MPEG-PCL micelles could be lyophilized without any adjuvant.The prepared honokiol formulation based on self-assembled MPEG-PCL micelle was stable, safe, effective, easy to produce and scale up, and showed potential clinical application.
Keywords: honokiol; Micelle; MPEG-PCL; nanomedicine; self-assembly

Semiparametric Distributions With Estimated Shape Parameters by Klas J. F. Petersson; Eva Hanze; Radojka M. Savic; Mats O. Karlsson (2174-2185).
To investigate the use of adaptive transformations to assess the parameter distributions in population modeling.The logit, box-cox, and heavy tailed transformations were investigated. Each one was used in conjunction with the standard (exponential) transformation for PK and PD parameters. The shape parameters of these transformations were estimated to allow the parameter distributions to more accurately resemble a wider range of parameter distributions. The transformations were tested both in simulated settings where the true distributions were known and in 30 models developed from real data.In the simulated setting the transformations were better than the standard lognormal distribution at characterizing the true distributions. Improvement could also be seen in objective function value (OFV) and in simulation based diagnostics. In the real datasets, significant model improvement based on OFV could be seen in 22, 18, and 22 out of the 30 models for the three transformations respectively.Transformations with estimated shape parameters are a promising approach to relax the often erroneous assumption of a known shape of the parameter distribution. They offer a simple and straightforward way of handling and characterizing parameter distributions.
Keywords: estimation; normality assumption; parameter distributions; population modeling; transformations

Stabilization of Peptide Vesicles by Introducing Inter-Peptide Disulfide Bonds by Albert J. van Hell; Daan J. A. Crommelin; Wim E. Hennink; Enrico Mastrobattista (2186-2193).
Previously, we have shown that the amphiphilic oligopeptide SA2 (Ac-Ala-Ala-Val-Val-Leu-Leu-Leu-Trp-Glu-Glu-COOH) spontaneously self-assemble into nano-sized vesicles in aqueous environment. Relative weak individual intermolecular interactions dominate such oligopeptide assemblies. In this study we aimed at improving the stability of such peptide vesicles by covalently crosslinking the oligopeptide vesicles using disulfide bonds. Two and three cysteines were introduced in the SA2 peptide sequence to allow crosslinking (Ac-Ala-Cys-Val-Cys-Leu-(Leu/Cys)-Leu-Trp-Glu-Glu-COOH).Upon disulfide formation the crosslinked vesicles remained stable under conditions that disrupted the non-crosslinked peptide vesicles. The stabilized vesicles were more closely examined in terms of particle size (distribution) using atomic force microscopy, cryogenic electron microscopy, as well as dynamic light scattering analysis, showing an average particle radius in number between 15 and 20 nm. Using entrapment of calcein it was shown that intermolecular crosslinking of peptides within the vesicles did not affect the permeability for calcein.Introduction of cysteines into the hydrophobic domain of the SA2 amphiphilic oligopeptides is a feasible strategy for crosslinking the peptide vesicles. Such small crosslinked oligopeptide vesicles may hold promise for drug delivery applications.
Keywords: amphiphilic oligopeptides; crosslinking; recombinant; self-assembly; vesicle

An Ex Vivo Toe Model Used to Assess Applicators for the Iontophoretic Ungual Delivery of Terbinafine by Anroop B. Nair; Hyun D. Kim; Shawn P. Davis; Robert Etheredge; Michael Barsness; Phillip M. Friden; S. Narasimha Murthy (2194-2201).
An ex vivo intact toe model was developed to assess two different applicator designs for iontophoretic delivery of terbinafine into the nail only or the nail and surrounding skin.Iontophoretic permeation studies were carried out on intact cadaver toes using nail-only and nail/skin applicators with a current dose of 10 mA*min (0.5 mA for 20 min).Iontophoresis enhanced drug permeation and tissue loading with both applicators tested. Greater drug delivery was observed with the nail/skin applicator due to the additional terbinafine being delivered directly through the lower impedance skin area surrounding the nail. The concentration of drug loaded into the contact area of the nail with the nail-only and nail/skin applicator was ~13 and ~7 fold higher than their respective passive delivery levels but equivalent from each other in total drug mass delivered over the whole nail plate. In vitro release of drug from the iontophoretically loaded nails into agar suggests that a single treatment could have a prolonged effect (>50 days).This study demonstrates that the ex vivo toe model was useful in assessing the functionality of the different applicator designs. These results suggest that iontophoresis can significantly enhance the delivery of drugs to both the hard and soft tissues of the toe for the treatment of onychomycosis and other nail disorders.
Keywords: applicator; iontophoretic; toe model; permeation; nail

To investigate the efficacy of polydisulfide-based biodegradable macromolecular contrast agents of different degradability and molecular weight for tumor characterization based on angiogenesis using dynamic contrast enhanced MRI (DCE-MRI).Biodegradable macromolecular MRI contrast agents, Gd-DTPA cystamine copolymers (GDCC) and Gd-DTPA cystine copolymers (GDCP), with molecular weight of 20 and 70 KDa were evaluated for tumor characterization. Gd(DTPA-BMA) and a prototype of macromolecular contrast agent, albumin-(Gd-DTPA), were used as controls. The DCE-MRI studies were performed in nude mice bearing MDA PCa 2b and PC-3 human prostate tumor xenografts. Tumor angiogenic kinetic parameters including endothelium transfer coefficient (Ktrans) and fractional tumor plasma volume (fPV) were calculated from the DCE-MRI data using a two-compartment model and compared between the two different tumor models for each contrast agent.There was no significant difference in the fPV values between two tumor models estimated with the same agent except for GDCC-70. The Ktrans values in both tumor models decreased with the increase of molecular weight of contrast agents. With the same high molecular weight (70 KDa), GDCC-70 showed a higher Ktrans values than GDCP-70 due to high degradability of the former in both tumor models (p < 0.05). The Ktrans values of MDA PCa 2b tumors were significantly higher than those of PC-3 tumors estimated by Gd(DTPA-BMA), GDCC-20, GDCC-70, GDCP-70, and albumin-(Gd-DTPA) (p < 0.05).The polydisulfide-based biodegradable macromolecular MRI contrast agents are promising in tumor characterization and differentiation with dynamic contrast enhanced MRI.
Keywords: biodegradable macromolecular contrast agent; dynamic contrast enhanced MRI; polydisulfides; tumor characterization

Recent studies suggest that polymorphisms in human carbonyl reductase 3 (CBR3) influence the pharmacodynamics of doxorubicin. First, we sought to identify the promoter of CBR3. Next, we examined whether two CBR3 promoter polymorphisms (CBR3 -725T>C and CBR3 -326T>A) dictate promoter activity and hepatic CBR3 mRNA levels.The promoter activities of CBR3 reporter constructs were investigated in HepG2 and MCF-7 cells. CBR3 mRNA levels were documented in 95 liver samples from white (n = 62) and black (n = 33) donors. Genotype-phenotype correlation analyses were used to determine the impact of the CBR3 -725T>C and CBR3 -326T>A polymorphisms on hepatic CBR3 mRNA levels.We identified the promoter of human CBR3. Liver samples from black donors showed higher relative CBR3 mRNA levels than samples from whites (CBR3 mRNAblacks = 3.0 ± 3.1 relative fold vs. CBR3 mRNAwhites = 1.6 ± 1.5 relative fold, p = 0.021). The variant -725C and -326A alleles did not modify the gene reporter activities of engineered CBR3 promoter constructs. In line, hepatic CBR3 mRNA levels were not associated with CBR3 -725T>C and CBR3 -326T>A genotype status.These studies provide the first insights into the regulation and variable hepatic expression of polymorphic CBR3.
Keywords: carbonyl reductase 3 (CBR3); ethnicity; gene promoter; liver; single nucleotide polymorphism

Predicting Inhibitors of Acetylcholinesterase by Regression and Classification Machine Learning Approaches with Combinations of Molecular Descriptors by Dmitriy Chekmarev; Vladyslav Kholodovych; Sandhya Kortagere; William J. Welsh; Sean Ekins (2216-2224).
Acetylcholinesterase (AChE) is both a therapeutic target for Alzheimer’s disease and a target for organophosphorus, carbamates and chemical warfare agents. Prediction of the likelihood of compounds interacting with this enzyme is therefore important from both therapeutic and toxicological perspectives.Support vector machine classification and regression models with molecular descriptors derived from Shape Signatures and the Molecular Operating Environment (MOE) application software were built and tested using a set of piperidine AChE inhibitors (N = 110).The combination of the alignment free Shape Signatures and 2D MOE descriptors with the Support Vector Regression method outperforms the models based solely on 2D and internal 3D (i3D) MOE descriptors, and is comparable with the best previously reported PLS model based on CoMFA molecular descriptors ( $$ { ext{r}}_{ ext{test,SVR}}^2 = 0.48 $$ vs. $$ { ext{r}}_{ ext{test,PLS}}^2 = 0.47 $$ from Sutherland et al. J Med Chem 47:5541–5554, 2004). Support Vector Classification algorithms proved superior to a classifier based on scores from the molecular docking program GOLD, with the overall prediction accuracies being QSVC(10CV) = 74% and QSVC(LNO) = 67% vs. QGOLD = 56%.These new machine learning models with combined descriptor schemes may find utility for predicting novel AChE inhibitors.
Keywords: acetylcholinesterase; docking; machine learning; molecular operating environment; quantitative structure activity relationship; shape signatures descriptors; support vector classification; support vector machine; support vector regression