In the process of new drug discovery, the application of virtual screening can enrich active compounds, reduce the cost of drug screening, and increase the feasibility of drug screening. Therefore virtual screening technology has become an important approach for new drug discovery. As virtual screening and bioactivity screening possess different advantages, their combination can effectively promote new drug discovery. In the present paper, the application and the trend of removal of non-drug compounds, removal of false positive compounds, pharmacophore searching, molecular docking, and molecular similarity in the process of drug discovery are introduced in order to obtain more benefit from virtual screening strategy for new drug discovery.
Drug Design ; Drug Discovery ; Drug Evaluation, Preclinical ; Models, Molecular

A simple model organism Caenorhabditis elegans has contributed substantially to the fundamental researches in biology. In an era of functional genomics, nematode worm has been developed into a multi-purpose tool that can be exploited to identify disease-causing or disease-associated genes, validate potential drug targets. This, coupled with its genetic amenability, low cost experimental manipulation and compatibility with high throughput screening in an intact physiological condition, makes the model organism into an effective toolbox for drug discovery. This review shows the unique features of C. elegans, how it can play a valuable role in our understanding of the molecular mechanism of human diseases and finding drug leads in drug development process.
Animals ; Caenorhabditis elegans ; Drug Discovery ; Drug Evaluation, Preclinical

Drug metabolism studies, including in vivo and in vitro metabolism studies, are significant in the design of candidate compounds and screening of lead compounds at drug discovery/development stages. Compared with in vivo metabolism studies, in vitro metabolism studies have the advantages of rapidity, simplicity, without consumption of large amounts of samples and animals. Moreover, it is convenient for researchers to observe the selective interaction between compound and target. Therefore, in vitro metabolism studies are appropriate for high throughput screening of compounds which are lack of metabolism information and have been widely used during drug discovery stages. This article briefly introduced the application of in vitro drug metabolism studies based on the metabolic stability, reaction phenotyping and metabolic drug-drug interactions, aiming to raise valuable evaluation strategies for innovative drug discovery in China.
Animals ; Cytochrome P-450 Enzyme System ; metabolism ; Drug Design ; Drug Discovery ; methods ; Drug Evaluation, Preclinical ; Drug Interactions ; Drug Stability ; Glucuronosyltransferase ; metabolism ; Humans ; Pharmaceutical Preparations ; metabolism ; Phenotype

Diversity-oriented synthesis (DOS) aims to efficiently generate collections of small molecules with diverse appendages, functional groups, stereochemistry and skeletons, thus yielding diverse biological activities capable of modulating a wide variety of biological processes. In this review, we discussed the common strategies employed in DOS with specific examples from recent literature, including reagent-based approach, substrate-based approach, build-couple-pair strategy and privileged substructure-based DOS. The application of some DOS libraries in drug discovery is also presented.
Drug Design ; Drug Discovery ; Small Molecule Libraries

The generation of induced pluripotent stem cells (iPSCs) derived from patients' somatic cells provides a new paradigm for studying human genetic diseases. Human iPSCs which have similar properties of human embryonic stem cells (hESCs) provide a powerful platform to recapitulate the disease-specific cell types by using various differentiation techniques. This promising technology has being realized the possibility to explore pathophysiology of many human genetic diseases at the molecular and cellular levels. Furthermore, disease-specific human iPSCs can also be used for patient-based drug screening and new drug discovery at the stage of the pre-clinical test in vitro. In this review, we summarized the concept and history of cellular reprogramming or iPSC generation and highlight recent progresses for disease modeling using patient-specific iPSCs.
Drug Discovery ; Drug Evaluation, Preclinical ; Embryonic Stem Cells ; Humans ; Induced Pluripotent Stem Cells ; Nuclear Reprogramming

The generation of induced pluripotent stem cells (iPSCs) derived from patients' somatic cells provides a new paradigm for studying human genetic diseases. Human iPSCs which have similar properties of human embryonic stem cells (hESCs) provide a powerful platform to recapitulate the disease-specific cell types by using various differentiation techniques. This promising technology has being realized the possibility to explore pathophysiology of many human genetic diseases at the molecular and cellular levels. Furthermore, disease-specific human iPSCs can also be used for patient-based drug screening and new drug discovery at the stage of the pre-clinical test in vitro. In this review, we summarized the concept and history of cellular reprogramming or iPSC generation and highlight recent progresses for disease modeling using patient-specific iPSCs.
Drug Discovery ; Drug Evaluation, Preclinical ; Embryonic Stem Cells ; Humans ; Induced Pluripotent Stem Cells ; Nuclear Reprogramming

Background: The biological activity of a compound is assumed to be encoded in its chemical composition and geometric structure, from which physico-chemical, electrotopological, and graph theory-derived properties can be determined. Objective: This study aimed to identify the molecular descriptors derived from Dragon® 6 software that can discriminate compounds as drug or nondrug Methodology: Over 4000 molecular properties were obtained for approximately 2000 known drugs and 2000 nondrugs on which Linear Discriminant Analysis was performed. Results: Compounds can be discriminated between drug and nondrug with 81% accuracy using only two molecular descriptors, the information index HVcpx and the topological index MDDD. Conclusion A “Rule of Three” (HVcpx ≤ 3 and MDDD ≥ 30) seems to confer druglikeness in compounds. This rule can be used as additional filter in high throughput screening of compounds in any drug discovery research.
Discriminant Analysis ; Drug Discovery

Currently available drugs for complex diseases have such limitations as unsatisfactory efficacy, drug resistance, and toxic side effects. Complexity of biological systems is a determinant of drug efficacy. It is not an effective approach to find disturbance strategies for the complicated biological network for complex diseases based on the static topological structures, as biological systems undergo dynamic changes all the time. Supported by profound theoretical basis and rich clinical experience, traditional Chinese medicine(TCM) emphasizes systematic and dynamic treatment depending on changes. Guided by TCM theory in practical treatment, Chinese medicine dynamically and comprehensively regulates the overall state. Therefore, if the dynamic factors are taken into consideration in design, the resultant drugs will be more effective. This study proposes state-regulating(SR) medicine from the perspective of system dynamics, elaborating the concept in terms of the connotations and principle and verifying the feasibility of SR medicine design with the attractor method. Thus, SR medicine is a new concept for drug discovery and design from the aspect of system dynamics, which integrates the TCM focusing on holistic dynamic regulation with biomedicine that features local microscopic research such as molecular mechanisms. The attractor method is a feasible techinical way for SR medicine design.
Drug Discovery ; Drugs, Chinese Herbal ; Medicine, Chinese Traditional ; Research Design

The nematode Caenorhabditis elegans (C. elegans) offers a unique opportunity for biological and basic medical researches due to its genetic tractability and well-defined developmental lineage. It also provides an exceptional model for genetic, molecular, and cellular analysis of human disease-related genes. Recently, C. elegans has been used as an ideal model for the identification and functional analysis of drugs (or small-molecules) in vivo. In this review, we describe conserved oncogenic signaling pathways (Wnt, Notch, and Ras) and their potential roles in the development of cancer stem cells. During C. elegans germline development, these signaling pathways regulate multiple cellular processes such as germline stem cell niche specification, germline stem cell maintenance, and germ cell fate specification. Therefore, the aberrant regulations of these signaling pathways can cause either loss of germline stem cells or overproliferation of a specific cell type, resulting in sterility. This sterility phenotype allows us to identify drugs that can modulate the oncogenic signaling pathways directly or indirectly through a high-throughput screening. Current in vivo or in vitro screening methods are largely focused on the specific core signaling components. However, this phenotype-based screening will identify drugs that possibly target upstream or downstream of core signaling pathways as well as exclude toxic effects. Although phenotype-based drug screening is ideal, the identification of drug targets is a major challenge. We here introduce a new technique, called Drug Affinity Responsive Target Stability (DARTS). This innovative method is able to identify the target of the identified drug. Importantly, signaling pathways and their regulators in C. elegans are highly conserved in most vertebrates, including humans. Therefore, C. elegans will provide a great opportunity to identify therapeutic drugs and their targets, as well as to understand mechanisms underlying the formation of cancer.
Caenorhabditis elegans* ; Drug Discovery* ; Drug Evaluation, Preclinical ; Germ Cells ; Humans ; Infertility ; Mass Screening ; Molecular Biology ; Neoplastic Stem Cells ; Phenotype ; Social Control, Formal ; Stem Cell Niche ; Stem Cells ; Vertebrates

Animals ; Betacoronavirus ; Coronavirus Infections ; drug therapy ; Drug Discovery ; Drug Evaluation, Preclinical ; Enzyme Inhibitors ; therapeutic use ; Humans ; Mice ; Molecular Structure ; Orthomyxoviridae Infections ; drug therapy ; Oseltamivir ; therapeutic use ; Oxidoreductases ; antagonists & inhibitors ; Pandemics ; Pneumonia, Viral ; drug therapy ; Pyrimidines ; biosynthesis