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This study may provide a clue to fully identify the molecular targets and elucidate the underlying mechanism of vancomycin-associated nephrotoxicity, resulting in an improved therapeutic effect and reduced side effect in clinical settings. Knowledge of protein-protein interactions and their binding sites is indispensable for in-depth understanding of the networks in living cells. With the avalanche of protein sequences generated in the postgenomic age, it is critical to develop computational methods for identifying in a timely fashion the protein-protein binding sites PPBSs based on the sequence information alone because the information obtained by this method can be used for both biomedical research and drug development.
To address such a challenge, Jianhua Jia, Bingxiang Liu, and colleagues [ 18 ] have proposed a new predictor, called iPPBS-Opt, in which they have used the concept of pseudo amino acid composition PseAAC [ 19 ] to formulate complicated protein sequences. Although there are many investigators see, e. The modification of cantharidinimide by means of the reaction of activated aziridine ring opening led to the discovery of a novel class of antitumor compounds.
They found that the most potent cytostatic compound, N -cantharidinimido-sulfamethazine, exhibited anti-HL and anti-Hep3B cell activities. Detailed results of their investigation are presented in the article [ 26 ]. In addition, the -F functional group is beneficial to CNS drugs, and the -NH 2 functional group is beneficial to anti-infective drugs and anti-cancer drugs; 3 the best R value intervals of candidate drugs are in the range of 0. They envision that the three chemical structure-related criteria may be applicable in a prospective manner for the identification of novel candidate drugs and will provide a theoretical foundation for designing new chemical entities with good drug-like properties.
For the purpose of finding highly active pyrazole amide compounds, Jin-Xia Mu, Xing-Hai Liu, Bao-Ju Li, and their coworkers designed and synthesized a series of novel pyrazole amide derivatives by multi-step reactions from phenylhydrazine and ethyl 3-oxobutanoate as starting materials.
They characterized the structures and antifungal activities of the title compounds and used DFT calculations to study the structure-activity relationships.
Residential School on Medicinal Chemistry and Biology in Drug Discovery (ResMed)
These articles not only provided important information, but also generated many useful tools for drug discovery and development. These works showed that the in vitro and in vivo experiments complemented with computation methods are continuously improving the effectiveness and efficiency of drug discovery processes to select lead candidates with more favorable pharmacological, pharmacokinetics, and toxicological profiles.
It is our intent that publication of this Special Issue can stimulate new strategies in drug design and provide new tools, approaches, and technologies to facilitate the evaluation of new drug candidates, leading to the rapid and successful development of novel, effective, and safe medicines for treating diseases [ 29 ]. National Center for Biotechnology Information , U. Journal List Molecules v. Published online Feb Derek J.
McPhee, Academic Editor. Author information Article notes Copyright and License information Disclaimer. Received Feb 8; Accepted Feb 9. Conflicts of Interest The authors declare no conflict of interest. References 1.
Zhong W. Molecular science for drug development and biomedicine. Xiao X. Luu K. AAPS J. Chopra G. Katsamakas S. Guo H. Radini I. Qin Y. Xie S. Zhao F. Liu D. Gouda A. Ihmaid S.
Jia J. Chou K. Pseudo amino acid composition and its applications in bioinformatics, proteomics and system biology. Ahmad K. Tahir M. Tiwari A. Dehzangi A. The biological functions of low-frequency phonons. Chen N. The biological functions of low-frequency phonons: 2.
Drug discovery - Wikipedia
Cooperative effects. Schwanke 1.
Siqueira 1. Calixto 1.
This review presents a historical overview of drug discovery and the non-clinical stages of the drug development process, from initial target identification and validation, through in silico assays and high throughput screening HTS , identification of leader molecules and their optimization, the selection of a candidate substance for clinical development, and the use of animal models during the early studies of proof-of-concept or principle. This report also discusses the relevance of validated and predictive animal models selection, as well as the correct use of animal tests concerning the experimental design, execution and interpretation, which affect the reproducibility, quality and reliability of non-clinical studies necessary to translate to and support clinical studies.
Collectively, improving these aspects will certainly contribute to the robustness of both scientific publications and the translation of new substances to clinical development. Key words: Non-clinical drug discovery and development; Target discovery and validation; Proof of principles; Animal research robustness.
The pharmaceutical industry, which involves an annual market of more than one trillion US dollars, has undergone remarkable progress regarding the development of new drugs. However, it is a relatively young industry of about 70 years.
Basic Principles of Drug Discovery and Development
The still prevailing concept regarding drug mechanisms of action was primordial in the creation of synthetic drugs and the subsequent growth of large pharmaceutical corporations. Many decades later from this initial concept, which provided the first indication of molecular targets, pharmacological receptors were discovered, allowing the development of most drugs currently on the market. With these events, the term "chemotherapy" also appeared.
It is important to note that Ehrlich was one of the first researchers to perform chemical synthesis in order to develop a drug to treat syphilis. Thus, in , in partnership with Hoechst, the scientist decided to carry out structural changes in substances called arsenobenzenes. After synthesizing substances, he discovered arsphenamine also known as compound , later named Salvarsan, which was used for the treatment of syphilis. In further studies with compound , Ehrlich designed the first protocols for the evaluation of clinical efficacy, which were distributed to several clinics in Germany, establishing the beginning of clinical research 1 , 2.
In the beginning of the 20th century, the world did not have drugs developed based on scientific research concerning safety toxicology and efficacy. Drugs were mainly derived from plants, with few substances of synthetic origin. In , the Food and Drug Administration FDA was established as the first agency to regulate the quality of food and medicine.
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However, at that time, the FDA was concerned only with limited aspects of drugs, such as their physical and chemical characteristics and their purity. Thus, drugs contaminated with heavy metals, such as mercury and arsenic, were often found. Substances such as morphine, cocaine, and many others that have been later banned in medicine, or that are currently under strict control, were freely marketed 3. These principles have been guiding scientific studies for the development of new drugs until today.
It was established that, prior to human administration, all new substances should have the following characteristics: well-established chemical composition, method of preparation and degree of purity; acute and prolonged toxicity tests assessed by repeated doses safety in different animal species; histopathology analysis in several animal organs, especially in kidneys and liver; known absorption and excretion mechanisms and drug tissue concentration; and known possible interactions with other substances and food.
From the Nuremberg Code landmark, the first multidisciplinary research groups arose, including physicians, pharmacologists, physiologists and chemists, which was the basis for the emergence of the large global pharmaceutical corporations. The first core of clinical research involving physicians and biostatisticians also emerged.
These were the main factors responsible for the extraordinary impulse observed in the field of new drug development, which enabled major advances in medical practice between and Drugs were developed based on the identification of new therapeutic targets, namely pharmacological receptors, as proposed earlier by Ehrlich. This was possible due to enormous advances in the basic sciences between and , mainly on cellular and molecular biology and medicinal chemistry. From this knowledge, new drugs could be developed against specific targets, and diseases of high prevalence, such as hypertension, schizophrenia, depression, hyperdyslipidemia, diabetes, cancer, and others, could be better controlled.
This approach can potentially lead to an identification of a molecule that modifies the disease phenotype through interaction or modulation of a previously undefined target receptors, transcription factors, cytoskeleton proteins, enzymes and others or simultaneously on multiple targets 6 , 9.