Validation of molecular docking programs for virtual screening against dihydropteroate synthase.

Dihydropteroate synthase (DHPS) is the target of the sulfonamide class of antibiotics and has been a validated antibacterial drug target for nearly 70 years. The sulfonamides target the p-aminobenzoic acid (pABA) binding site of DHPS and interfere with folate biosynthesis and ultimately prevent bacterial replication. However, widespread bacterial resistance to these drugs has severely limited their effectiveness. This study explores the second and more highly conserved pterin binding site of DHPS as an alternative approach to developing novel antibiotics that avoid resistance. In this study, five commonly used docking programs, FlexX, Surflex, Glide, GOLD, and DOCK, and nine scoring functions, were evaluated for their ability to rank-order potential lead compounds for an extensive virtual screening study of the pterin binding site of B. anthracis DHPS. Their performance in ligand docking and scoring was judged by their ability to reproduce a known inhibitor conformation and to efficiently detect known active compounds seeded into three separate decoy sets. Two other metrics were used to assess performance; enrichment at 1% and 2% and Receiver Operating Characteristic (ROC) curves. The effectiveness of postdocking relaxation prior to rescoring and consensus scoring were also evaluated. Finally, we have developed a straightforward statistical method of including the inhibition constants of the known active compounds when analyzing enrichment results to more accurately assess scoring performance, which we call the 'sum of the sum of log rank' or SSLR. Of the docking and scoring functions evaluated, Surflex with Surflex-Score and Glide with GlideScore were the best overall performers for use in virtual screening against the DHPS target, with neither combination showing statistically significant superiority over the other in enrichment studies or pose selection. Postdocking ligand relaxation and consensus scoring did not improve overall enrichment.

The role of AA sponsors: a pilot study.

AIMS: The aim of this study was to explore the roles of Alcoholics Anonymous (AA) sponsors and to describe the characteristics of a sample of sponsors. METHODS: Twenty-eight AA sponsors, recruited using a purposive sampling method, were administered an unstructured qualitative interview and standardized questionnaires. The measurements included: a content analysis of sponsors' responses; Severity of Alcohol Dependence Questionnaire-Community version (SADQ-C) and Alcoholics Anonymous Affiliation Scale (AAAS). RESULTS: Sample characteristics were as follows: the median length of AA attendance was 9.5 years (range 5-28); the median length of sobriety was 11 years (range 4.5-28); the median number of sponsees per sponsor was 1 but there was a wide range (0-17, interquartile range 3.75); and the sponsors were highly affiliated to AA (median AAAS score 8.75, range 5.5-8.75, maximum possible score 9). Past alcohol dependence scores were surprisingly low: 5 (18%) sponsors had mild, 14 (50%) moderate and 9 (32%) severe dependence according to the SADQ-C (median 26.5, range 11-56). Sponsorship roles were as follows: 16 roles were identified through the initial content analysis. These were distilled into three super-ordinate roles through a thematic analysis: (1) encouraging sponsees to work the programme of AA (doing the 12 steps and engaging in AA activity); (2) support (regular contact, emotional support and practical support); and (3) carrying the message of AA (sharing sponsor's personal experience of recovery with sponsees). CONCLUSIONS: The roles identified broadly corresponded with the AA literature delineating the duties of a sponsor. This non-random sample of sponsors was highly engaged in AA activity but only had a past history of moderate alcohol dependence.

Quantitative structure-activity relationship studies on nitrofuranyl anti-tubercular agents.

A series of nitrofuranylamide and related aromatic compounds displaying potent activity against Mycobacterium tuberculosis have been investigated utilizing 3-dimensional quantitative structure-activity relationship (3D-QSAR) techniques. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods were used to produce 3D-QSAR models that correlated the minimum inhibitory concentration (MIC) values against M. tuberculosis with the molecular structures of the active compounds. A training set of 95 active compounds was used to develop the models, which were then evaluated by a series of internal and external cross-validation techniques. A test set of 15 compounds was used for the external validation. Different alignment and ionization rules were investigated as well as the effect of global molecular descriptors including lipophilicity (cLogP, LogD), polar surface area (PSA), and steric bulk (CMR), on model predictivity. Models with greater than 70% predictive ability, as determined by external validation, and high internal validity (cross-validated r(2)>.5) have been developed. Incorporation of lipophilicity descriptors into the models had negligible effects on model predictivity. The models developed will be used to predict the activity of proposed new structures and advance the development of next generation nitrofuranyl and related nitroaromatic anti-tuberculosis agents.

Association analysis of SOD2 variants with methamphetamine psychosis in Japanese and Taiwanese populations.

SOD2 (superoxide dismutase 2) plays a crucial role in protecting the cells against damage caused by free radicals, by catalyzing their detoxification. On the other hand, cell damage caused by free radical generation following methamphetamine administration has been postulated as one of the possible pathophysiological mechanisms for methamphetamine psychosis. Hence, we investigated the association of SOD2 polymorphisms with the development of methamphetamine psychosis, in two independent populations of Japan and Taiwan. We recruited 116 patients with methamphetamine psychosis and 189 controls in Japan, and 135 patients with methamphetamine psychosis and 204 controls in Taiwan. The methamphetamine group was divided into two clinical subtypes: a transient type of psychosis (i.e., good prognosis) and a prolonged type of psychosis (i.e., poor prognosis), according to the course of the manifestation of psychosis. With reference to the genotypic and allelic frequencies of Ala/Val functional polymorphism in exon 2, we found significant differences between individuals with prolonged methamphetamine psychosis and control samples from Japan and Taiwan in the genotypic (P value 0.014 and 0.016, respectively) and in the allelic (P value 0.004 and 0.047, respectively) frequencies. Our results suggest that Ala/Val polymorphism of the SOD2 gene could be associated with the risk of developing methamphetamine psychosis.

Association analysis of dopamine D2-like receptor genes and methamphetamine abuse.

OBJECTIVES: Substance use disorders are familial, and genetic factors explain a substantial degree of their familial aggregation. This study employs an association approach to examine the genetic underpinning of methamphetamine (MAMP) use and MAMP-induced psychosis. METHODS: A total of 416 MAMP abusers from a hospital and a detention center in Taipei were interviewed with the Diagnostic Interview for Genetic Study and the Family Interview for Genetic Study. Genetic polymorphisms of D2-like dopamine receptor genes, DRD2 TaqI A, DRD3 Ser-9-Gly, and DRD4 exon III variable number of tandem repeats, were compared between: (a) MAMP users as a whole and 435 normal controls, and (b) those 154 individuals with MAMP-induced psychosis and the 252 MAMP users with no psychosis. RESULTS: None of the three markers we studied were associated with predisposition to psychosis among the MAMP abusers. The MAMP abusers had a higher (P=0.011) prevalence of the seven-repeat allele of DRD4 than normal controls. CONCLUSIONS: Chance fluctuations in the frequency of rare alleles and ascertainment differences in the case and control samples cannot be ruled out. Therefore, further studies of the seven-repeat allele in MAMP abusers and controls should be performed before an association can be established.

Increasing practice nurse access to alcohol training.

Policy makers have repeatedly placed emphasis on the role of primary care in screening for at-risk alcohol consumption and delivering public health messages to the general population. Research has pointed to primary care staff holding negative attitudes towards alcohol misusing patients. Training has traditionally been seen as the key to increasing the capacity of the medical field to engage with alcohol misusing patients but little work has been undertaken to examine the potential barriers to training take up. Consequently, the aim of this study was to explore the willingness of practice nurses to be trained in alcohol screening and brief intervention, and whether identifiable barriers to training exist and how they may be overcome. All practice nurses (n = 82) in an outer London (UK) Health Authority Area were twice mailed an invitation to an alcohol training seminar and a telephone invitation was made to all of those who did not reply to the mailings. Those who did not attend (n = 66) were contacted to take part in a short structured telephone interview - 89% (59/66) were contacted successfully and interviewed. Respondents were experienced in primary care and viewed health promotional activity as a valid part of their role. Few had undertaken previous alcohol training and as a group they were highly active in attending training events with training undertaken tending to be related directly to perceived practice needs and priorities: thus this group could not be characterized as unwilling to be trained. Barriers to training at alcohol events were found to be either personal or work-related, with most nurses interested in receiving further training or information. These data imply that the ways in which training is organized and delivered require sensitivity to identifiable barriers if it is to reach and effect changing practice among practice nurses successfully. A range of possibilities are identified as alternative approaches to the provision of elective training events which may be more acceptable to the target population of health-care staff.

Allelic association analysis of the dopamine D2, D3, 5-HT2A, and GABA(A)gamma2 receptors and serotonin transporter genes with heroin abuse in Chinese subjects.

Five candidate genes, the receptors DRD2, DRD3, HTR2A and GABA(A)gamma2, and the serotonin transporter (5-HTT) were analyzed for association with heroin abuse. We examined three polymorphisms (promoter - 141DeltaC, Ser311Cys, and TaqI) in the DRD2 gene, one polymorphism (Ser9Gly) in the DRD3 gene, two polymorphisms (promoter - 1438G/A and T102C) in the HTR2A gene, two polymorphisms (VNTR and Del/Ins) in 5-HTT gene, and one polymorphism (G3145A) in GABA(A)gamma2 gene in 121 Chinese heroin addicts and 194 controls. None of the polymorphisms differed significantly for allele, genotype, or haplotype frequencies, except for the DRD2 promoter polymorphism - 141DeltaC (genotype-wise and allele-wise, P = 0.05, uncorrected). An additional 344 subjects with heroin abuse and 104 controls were investigated for the - 141DeltaC polymorphism. In the second sample, there were no significant difference of genotype or allele frequencies between subjects with heroin abuse and normal controls. When we divided the sample by route of administration into nasal inhalers and IM or IV injectors, however, it produced a significant difference between inhalers of heroin and controls (genotype-wise, P = 0.006, allele-wise, P = 0.016) but not for injectors of heroin (genotype-wise, P = 0.81, allele-wise, P = 0.69). We also found that LD between all polymorphisms we examined in the gene was weak, possibly explaining why we see association of this polymorphism with heroin abuse but not with other markers in the gene. Overall our results indicates that the HTR2A, 5-HTT, DRD3 and GABA(A)gamma2 genes are not likely to be a major genetic risk factor for heroin abuse in this population, with the exception of possible association between nasal inhalation and DRD2 promoter - 141DeltaC polymorphism.