Quantitative surface field analysis: learning causal models to predict ligand binding affinity and pose.

We introduce the QuanSA method for inducing physically meaningful field-based models of ligand binding pockets based on structure-activity data alone. The method is closely related to the QMOD approach, substituting a learned scoring field for a pocket constructed of molecular fragments. The problem of mutual ligand alignment is addressed in a general way, and optimal model parameters and ligand poses are identified through multiple-instance machine learning. We provide algorithmic details along with performance results on sixteen structure-activity data sets covering many pharmaceutically relevant targets. In particular, we show how models initially induced from small data sets can extrapolatively identify potent new ligands with novel underlying scaffolds with very high specificity. Further, we show that combining predictions from QuanSA models with those from physics-based simulation approaches is synergistic. QuanSA predictions yield binding affinities, explicit estimates of ligand strain, associated ligand pose families, and estimates of structural novelty and confidence. The method is applicable for fine-grained lead optimization as well as potent new lead identification

Electrostatic-field and surface-shape similarity for virtual screening and pose prediction.

We introduce a new method for rapid computation of 3D molecular similarity that combines electrostatic field comparison with comparison of molecular surface-shape and directional hydrogen-bonding preferences (called "eSim"). Rather than employing heuristic "colors" or user-defined molecular feature types to represent conformation-dependent molecular electrostatics, eSim calculates the similarity of the electrostatic fields of two molecules (in addition to shape and hydrogen-bonding). We present detailed virtual screening performance data on the standard 102 target DUD-E set. In its moderately fast screening mode, eSim running on a single computing core is capable of processing over 60 molecules per second. In this mode, eSim performed significantly better than all alternate methods for which full DUD-E data were available (mean ROC area of 0.74, p [Formula: see text], by paired t-test, compared with the best performing alternate method). In addition, for 92 targets of the DUD-E set where multiple ligand-bound crystal structures were available, screening performance was assessed using alternate ligands or sets thereof (in their bound poses) as similarity targets. Using the joint alignment of five ligands for each protein target, mean ROC area exceeded 0.82 for the 92 targets. Design-focused application of ligand similarity methods depends on accurate predictions of geometric molecular relationships. We comprehensively assessed pose prediction accuracy by curating nearly 400,000 bound ligand pose pairs across the DUD-E targets. Overall, beginning from agnostic initial poses, we observed an 80% success rate for RMSD [Formula: see text] Å  among the top 20 predicted eSim poses. These examples were split roughly 50/50 into cases with high direct atomic overlap (where a shared scaffold exists between a pair) and low direct atomic overlap (where where a ligand pair has dissimilar scaffolds but largely occupies the same space). Within the high direct atomic overlap subset, the pose prediction success rate was 93%. For the more challenging subset (where dissimilar scaffolds are to be aligned), the success rate was 70%. The eSim approach enables both large-scale screening and rational design of ligands and is rooted in physically meaningful, non-heuristic, molecular comparisons

Recommendations for evaluation of computational methods

The field of computational chemistry, particularly as applied to drug design, has become increasingly important in terms of the practical application of predictive modeling to pharmaceutical research and development. Tools for exploiting protein structures or sets of ligands known to bind particular targets can be used for binding-mode prediction, virtual screening, and prediction of activity. A serious weakness within the field is a lack of standards with respect to quantitative evaluation of methods, data set preparation, and data set sharing. Our goal should be to report new methods or comparative evaluations of methods in a manner that supports decision making for practical applications. Here we propose a modest beginning, with recommendations for requirements on statistical reporting, requirements for data sharing, and best practices for benchmark preparation and usage

Complex macrocycle exploration: parallel, heuristic, and constraint-based conformer generation using ForceGen.

ForceGen is a template-free, non-stochastic approach for 2D to 3D structure generation and conformational elaboration for small molecules, including both non-macrocycles and macrocycles. For conformational search of non-macrocycles, ForceGen is both faster and more accurate than the best of all tested methods on a very large, independently curated benchmark of 2859 PDB ligands. In this study, the primary results are on macrocycles, including results for 431 unique examples from four separate benchmarks. These include complex peptide and peptide-like cases that can form networks of internal hydrogen bonds. By making use of new physical movements ("flips" of near-linear sub-cycles and explicit formation of hydrogen bonds), ForceGen exhibited statistically significantly better performance for overall RMS deviation from experimental coordinates than all other approaches. The algorithmic approach offers natural parallelization across multiple computing-cores. On a modest multi-core workstation, for all but the most complex macrocycles, median wall-clock times were generally under a minute in fast search mode and under 2 min using thorough search. On the most complex cases (roughly cyclic decapeptides and larger) explicit exploration of likely hydrogen bonding networks yielded marked improvements, but with calculation times increasing to several minutes and in some cases to roughly an hour for fast search. In complex cases, utilization of NMR data to constrain conformational search produces accurate conformational ensembles representative of solution state macrocycle behavior. On macrocycles of typical complexity (up to 21 rotatable macrocyclic and exocyclic bonds), design-focused macrocycle optimization can be practically supported by computational chemistry at interactive time-scales, with conformational ensemble accuracy equaling what is seen with non-macrocyclic ligands. For more complex macrocycles, inclusion of sparse biophysical data is a helpful adjunct to computation

Migration/mobility and vulnerability to HIV among male migrant workers: Maharashtra 2007-08

HIV prevalence in Maharashtra is one of the highest among Indian states. The specific objectives of this study were: to understand the patterns and drivers of migration/mobility of men who migrate for the purpose of work in the state of Maharashtra; to describe the characteristics of vulnerable subpopulations among migrant men; and to examine the determinants of high-risk sexual behavior among the subpopulations of migrant men with particular emphasis on the role of mobility in determining the sexual risk behavior. The present study clearly demonstrates that these male migrants, married or otherwise, retain strong connectivity to their native villages, but also show high levels of sexual activity—including significant levels of high-risk sexual activity—making it imperative to study the situation in the sending districts regarding HIV prevalence and spread. The indication from this study is clear: in the context of high-risk sexual behavior (among both married and unmarried migrants) and the low levels of knowledge, condom use, and risk perception, the chances of sending households and districts becoming areas of high HIV prevalence are great. Further exploration of the sexual behavior pattern in sending areas is necessary to obtain additional insights into the possible routes of HIV transmission

Migration/mobility and vulnerability to HIV among male migrant workers: Karnataka 2007-08

The present study was undertaken by the Population Council and the Karnataka Health Promotion Trust to study the patterns and factors driving migration among men and the extent to which they engage in high-risk activities associated with HIV. The specific objectives of the study were: to understand the patterns and factors driving the migration of men seeking work in the state of Karnataka; to describe the characteristics of vulnerable subpopulations among migrant men; and to examine the determinants of high-risk sexual behavior among the subpopulations of migrant men, with an emphasis on their mobility as one possible factor. Results suggest no relationship between degree of mobility and risky sexual behaviors among the migrants surveyed, and no systematic pattern of a relationship between condom use with the various types of sex partners and degree of mobility, indicating the need for HIV-prevention initiatives in their home areas as well as in their work destinations. Future research is needed to improve understanding of the behavior of men working in specific occupational groups in terms of their sexual networks and HIV-prevention needs

Validation of the CREST score for predicting circulatory-aetiology death in out-of-hospital cardiac arrest without STEMI

Aims: The CREST tool was recently developed to stratify the risk of circulatory-aetiology death (CED) in out-of-hospital cardiac arrest (OHCA) patients without ST-elevation myocardial infarction (STEMI). We aimed to validate the CREST score using an external cohort and determine whether it could be improved by the addition of serum lactate on admission. Methods: The study involved the retrospective analysis of consecutive patients admitted to a single tertiary centre with OHCA of presumed cardiac origin over a 51-month period. The CREST score was calculated by attributing points to the following variables: Coronary artery disease (CAD), non-shockable Rhythm, Ejection fraction <30%, cardiogenic Shock at presentation and ischaemic Time ≥25 minutes. The primary endpoint was CED vs neurological aetiology death (NED) or survival. Results: Of 500 patients admitted with OHCA, 211 did not meet criteria for STEMI and were included. 115 patients died in hospital (71 NED, 44 CED). When analysed individually, CED was associated with all CREST variables other than a previous diagnosis of CAD. The CREST score accurately predicted CED with excellent discrimination (C-statistic 0.880, 95% CI 0.813-0.946) and calibration (Hosmer and Lemeshow P=0.948). Although an admission lactate ≥7 mmol/L also predicted CED, its addition to the CREST score (the C-AREST score) did not significantly improve the predictive ability (CS 0.885, 0.815-0.954, HS P=0.942, X2 difference in -2 log likelihood =0.326, P=0.850). Conclusion: Our study is the first to independently validate the CREST score for predicting CED in patients presenting with OHCA without STEMI. Addition of lactate on admission did not improve its predictive ability.Publisher PDFPeer reviewe

Patterns of migration/mobility and HIV risk among female sex workers: Tamil Nadu 2007-08

In past years, considerable research has been undertaken on the role of female sex workers (FSWs) in the transmission of HIV infection. FSWs have been seen as a major “source” of infection, and consequently, have been extensively targeted to prevent its spread. There is, however, a gap in our understanding of the dynamics of sex work, sex workers\u27 patterns of mobility, and the relationship of such mobility with risk of HIV infection and gender-based violence. The Population Council collaborated with its local partner, TNS, to carry out a study in Tamil Nadu to examine the patterns of mobility of FSWs and to study its links with HIV risk. The goal was to provide research-based evidence to inform the formulation of policies and to improve the implementation of programs. Results presented here describe the patterns and drivers of sex workers\u27 migration at their destination points, intermediate points, and points of origin, and their connection to high-risk activities in Tamil Nadu

Migration/mobility and vulnerability to HIV among male migrant workers: Andhra Pradesh 2007-08

The Population Council, in collaboration with TNS India Pvt. Ltd., undertook a study in Andhra Pradesh, India, to examine the patterns of male migration and its links with HIV risk. The goal was to provide evidence to inform the design and implementation of HIV interventions for male migrant workers. The study documented the volume and patterns of mobility, including the social dynamics within the contract system that employs these men as laborers, and the sexual risk behaviors and addictive behaviors of male migrants. The results suggest a predominance of interdistrict movements of men within Andhra Pradesh with a strong positive association between individuals\u27 degree of mobility and their sexual behavior. Moreover, an increase in degree of mobility is linked to inconsistent or nonuse of condoms, and there is limited knowledge of HIV infection among these recent male migrants. The study shows that there is a clear need for implementing interventions to prevent HIV infection in migrant workers and the authors of this report recommend the use of work-contract systems for delivering HIV-prevention interventions

Patterns of migration/mobility and HIV risk among female sex workers: Maharashtra 2007-08

According to recent estimates, Maharashtra, India recorded high HIV prevalence among female sex workers, however there is a dearth of research documenting the migration patterns of sex workers and the linkages between their mobility and vulnerability to HIV. This Population Council study attempts to answer some of the questions on mobility and migration of female sex workers in Maharashtra as they relate to the HIV epidemic. Findings show an association between degree of mobility and the indicators of HIV risk such as consistent condom use with different types of partners, STI symptoms reported, sexual violence, and self-perception of risk for HIV. Targeting such a highly mobile population of female sex workers who appear to be vulnerable to HIV requires a comprehensive understanding of their places of solicitation and sex. Programs that want to ensure better coverage of their interventions should focus on five major places: brothels, railway/bus stations, dhabas, bars, and hotels/lodges