Current opinion in drug discovery & development最新文献

In the past decade, intensive efforts have focused on the discovery of both nucleos(t)ide and non-nucleoside inhibitors of the HCV NS5B polymerase. These efforts have resulted in several promising agents advancing in clinical development. This review traces the history of optimization of the chemical series that have led to the development of clinical candidates, and summarizes recent developments in the field, with emphasis on clinical efficacy and impact for future combination studies.

The ranking of ligand docking poses according to certain scoring systems to identify the best fit is the most important step in virtual database screening for drug discovery. By focusing on method development strategy, this review provides possibilities for constructing rescoring approaches based on an overview of recent developments in the field. These developments can be classified into three categories. The first category involves a scaling approach that employs a factor to scale the primary scoring function. These scaling factors are defined with respect to the geometrical match between the location of a ligand and the target binding site, or defined according to a molecular weight distribution consistent with the empirical range of molecular weights of drug-like compounds. The second category involves consensus scoring approaches that use multiple scoring functions to rank the ligand poses retained in a docking procedure, based on the preliminary ranking according to a primary scoring function. The final category involves the addition of selected accuracy-oriented energy terms, such as the solvent effect and quantum mechanics/molecular mechanics treatments.

The traditional understanding that proteins are the only effectors of gene function has been challenged by the discovery of a group of genes that do not encode proteins (non-coding genes [ncGs]). The role of ncGs in the pathogenesis and potentially the treatment of several human diseases is increasingly being confirmed. A robust collection of literature exists to support the theory of the involvement of ncGs and their non-coding RNA (ncRNA) transcripts in the pathogenesis of cancer. This review focuses on the role of ncRNAs in human carcinogenesis and describes why deciphering the function of these RNAs might lead to the development of new anticancer drugs.

GPCRs are key components of signal transduction pathways and are important drug targets. Recently determined GPCR structures provide opportunities for advancements in GPCR modeling. This review focuses on the choice of experimental templates, the treatment of extracellular loops and the description of ligand-binding sites in GPCR modeling. Four important conclusions are reached in this review: (i) multi-template models may produce better structures than single-template models, although inferior models may also be generated by multi-template approaches, warranting the development and application of improved model assessment methods; (ii) cautious incorporation of knowledge-based constraints can improve the quality of models and docking; (iii) molecular dynamics simulations account for structural features not observed in X-ray structures and may refine docking poses; and (iv) while progress in de novo methods for long loop prediction is ongoing, loopless models provide a practical alternative for docking and virtual screening applications.

Many different public and private organizations from across the globe are collaborating on neglected diseases drug-discovery and development projects with the aim of identifying a cure for tropical infectious diseases. These neglected diseases collaborations require a global, secure, multi-organization data-management solution, combined with a platform that facilitates communication and supports collaborative work. This review discusses the solutions offered by 'Software as a Service' (SaaS) web-based platforms, despite notable challenges, and the evolution of these platforms required to foster efficient virtual research efforts by geographically dispersed scientists.

Rational drug design relies on the 3D structures of biological macromolecules, with a particular emphasis on proteins. The structural genomics-based high-throughput structure determination platforms established by the Protein Structure Initiative (PSI) of the National Institute of General Medical Science (NIGMS) of the NIH are uniquely suited to provide these structures. NMR plays a critical role in structure determination because many important protein targets do not form the single crystals required for X-ray diffraction. NMR can provide valuable structural and dynamic information on proteins and their drug complexes that cannot be obtained with X-ray crystallography. This review discusses recent advances in NMR that have been driven by structural genomics projects. These advances suggest that the future discovery and design of drugs can increasingly rely on protocols using NMR approaches for the rapid and accurate determination of structures.

Changes in the understanding of biological science, translational research and corporate business models require a corresponding change in the approach to chemical and biological information management. The concept of operations being partitioned into discrete departments for drug discovery is beginning to be replaced by a translational approach to this process. Pharmaceutical business and organizational models are also constantly evolving. Traditional approaches to transactional systems, transferring data up to a departmental data warehouse, are no longer meeting the needs of pharmaceutical scientists and, thus, IT departments are not considered as relevant to the business. These changes and their impact on information systems, as well as some solutions to the challenges faced, are discussed in this editorial.

Cloud computing provides information processing power and business services, delivering these services over the Internet from centrally hosted locations. Major technology corporations aim to supply these services to every sector of the economy. Deploying business processes 'in the cloud' requires special attention to the regulatory and business risks assumed when running on both hardware and software that are outside the direct control of a company. The identification of risks at the correct service level allows a good mitigation strategy to be selected. The pharmaceutical industry can take advantage of existing risk management strategies that have already been tested in the finance and electronic commerce sectors. In this review, the business risks associated with the use of cloud computing are discussed, and mitigations achieved through knowledge from securing services for electronic commerce and from good IT practice are highlighted.

Researchers investigating many areas of disease recognize the value of integrating large-scale genomic experiments across species and experimental methods. Analysis methods have been developed to make use of the breadth and depth of data from new technologies. Current paradigms of data storage, sharing and analysis are not yet ideal for these purposes. Open-access and analysis-enabled repositories are critical to progress, as they put the global integration of genomic data within reach of individual expert investigators. Current analytic approaches use the full scale and scope of data, but require data sharing, interoperability and community recognition of the value of shared information.