Reverse pharmacology

About: Reverse pharmacology is a research topic. Over the lifetime, 349 publications have been published within this topic receiving 17220 citations.

Target-oriented and diversity-oriented organic synthesis in drug discovery.

Abstract: Modern drug discovery often involves screening small molecules for their ability to bind to a preselected protein target. Target-oriented syntheses of these small molecules, individually or as collections (focused libraries), can be planned effectively with retrosynthetic analysis. Drug discovery can also involve screening small molecules for their ability to modulate a biological pathway in cells or organisms, without regard for any particular protein target. This process is likely to benefit in the future from an evolving forward analysis of synthetic pathways, used in diversity-oriented synthesis, that leads to structurally complex and diverse small molecules. One goal of diversity-oriented syntheses is to synthesize efficiently a collection of small molecules capable of perturbing any disease-related biological pathway, leading eventually to the identification of therapeutic protein targets capable of being modulated by small molecules. Several synthetic planning principles for diversity-oriented synthesis and their role in the drug discovery process are presented in this review.

Human Disease Models in Drosophila melanogaster and the Role of the Fly in Therapeutic Drug Discovery

Abstract: The common fruit fly, Drosophila melanogaster, is a well studied and highly tractable genetic model organism for understanding molecular mechanisms of human diseases. Many basic biological, physiological, and neurological properties are conserved between mammals and D. melanogaster, and nearly 75% of human disease-causing genes are believed to have a functional homolog in the fly. In the discovery process for therapeutics, traditional approaches employ high-throughput screening for small molecules that is based primarily on in vitro cell culture, enzymatic assays, or receptor binding assays. The majority of positive hits identified through these types of in vitro screens, unfortunately, are found to be ineffective and/or toxic in subsequent validation experiments in whole-animal models. New tools and platforms are needed in the discovery arena to overcome these limitations. The incorporation of D. melanogaster into the therapeutic discovery process holds tremendous promise for an enhanced rate of discovery of higher quality leads. D. melanogaster models of human diseases provide several unique features such as powerful genetics, highly conserved disease pathways, and very low comparative costs. The fly can effectively be used for low- to high-throughput drug screens as well as in target discovery. Here, we review the basic biology of the fly and discuss models of human diseases and opportunities for therapeutic discovery for central nervous system disorders, inflammatory disorders, cardiovascular disease, cancer, and diabetes. We also provide information and resources for those interested in pursuing fly models of human disease, as well as those interested in using D. melanogaster in the drug discovery process.

Structure-based virtual screening for drug discovery: principles, applications and recent advances.

Abstract: Structure-based drug discovery (SBDD) is becoming an essential tool in assisting fast and cost-efficient lead discovery and optimization. The application of rational, structure-based drug design is proven to be more efficient than the traditional way of drug discovery since it aims to understand the molecular basis of a disease and utilizes the knowledge of the three-dimensional structure of the biological target in the process. In this review, we focus on the principles and applications of Virtual Screening (VS) within the context of SBDD and examine different procedures ranging from the initial stages of the process that include receptor and library pre-processing, to docking, scoring and post-processing of topscoring hits. Recent improvements in structure-based virtual screening (SBVS) efficiency through ensemble docking, induced fit and consensus docking are also discussed. The review highlights advances in the field within the framework of several success studies that have led to nM inhibition directly from VS and provides recent trends in library design as well as discusses limitations of the method. Applications of SBVS in the design of substrates for engineered proteins that enable the discovery of new metabolic and signal transduction pathways and the design of inhibitors of multifunctional proteins are also reviewed. Finally, we contribute two promising VS protocols recently developed by us that aim to increase inhibitor selectivity. In the first protocol, we describe the discovery of micromolar inhibitors through SBVS designed to inhibit the mutant H1047R PI3Kα kinase. Second, we discuss a strategy for the identification of selective binders for the RXRα nuclear receptor. In this protocol, a set of target structures is constructed for ensemble docking based on binding site shape characterization and clustering, aiming to enhance the hit rate of selective inhibitors for the desired protein target through the SBVS process.

Ayurveda and natural products drug discovery

Abstract: This review attempts to portray the discovery and development of medicine from galenical to genomical, with a focus on the potential and role of ayurveda. Natural products, including plants, animals and minerals have beenthe basis of treatment of human diseases. Indigenous people derived therapeutic materials from thousands of plants; however discovering medicines or poisons remains a vital question. Ayurveda is a traditional Indian medicinal system being practised for thousands of years. Considerable research on pharmacognosy, chemistry, pharmacology and clinical therapeutics has been carried out on ayurvedic medicinal plants. Many of the major pharmaceutical corporations have renewed their strategies in favour of natural products drug discovery and it is important to follow systems biology applications to facilitate the process. Numerous drugs have entered the international pharmacopoeia through the study of ethnopharmacology and traditional medicine. For ayurveda and other traditional medicines newer guidelines of standardization, manufacture and quality control are required. Employing a unique holistic approach, ayurvedic medicines are usually customized to an individual constitution. Traditional knowledge-driven drug development can follow a reverse pharmacology path and reduce time and cost of development. New approaches to improve and accelerate the joint drug discovery and development process are expected to take place mainly from innovation in drug target elucidation and lead structure discovery. Powerful new technologies such as automated separation techniques, high-throughput screening and combinatorial chemistry are revolutionizing drug discovery. Traditional knowledge will serve as a powerful search engine and most importantly, will greatly facilitate intentional, focused and safe natural products research to rediscover the drug discovery process.