Practice Of Medicinal Chemistry Research Articles

In silico applications of bioisosterism in contemporary medicinal chemistry practice

AbstractBioisosterism is a key concept in medicinal chemistry, as it allows medicinal chemists to interchange structural fragments without significant perturbation in biological activity. Not surprisingly, given the vast amount of bioactivity data and chemoinformatics resources now available, there has been a significant surge in the number of computational approaches available to mine and identify bioisosteric replacements for fragments of bioactive compounds. Such methods have certainly provided medicinal chemists with a diverse arsenal of in‐house, commercial, and academic tools and interfaces to aid in the optimization across a number of end points such as bioactivity; selectivity; and absorption, distribution, metabolism, excretion, and toxicity properties for effective and efficient drug design. These in silico bioisosteric replacement mining approaches can generally be divided into two categories, namely ligand based and structure based. The approaches of the former category use information that is derived from ligands, whereas the latter category requires knowledge of the biological target, as well as specific knowledge of the interactions between ligand and target in the binding pocket. Ligand‐based methodologies are also typically divided into similarity‐based and database mining (or knowledge‐based) approaches. In general, the former provide an assessment of putative bioisosteric fragments and substructures, in terms of molecular topology and descriptors, whereas the latter extract structural transformations from large chemical repositories and associate them with the induced change in biological or any other property of interest. Following systematic retrospective studies, a large number of nonclassical bioisosteric equivalents have been reported in the literature.This article is categorized under: Computer and Information Science > Chemoinformatics

Synthesis, anti-inflammatory, and structure antioxidant activity relationship of novel 4-quinazoline

The practice of medicinal chemistry is devoted to the discovery and development of new agents for treating disease. A new derivative of methyl 2-((E)-3-(3,4-dihydroxyphenyl)acrylamido)benzoate 2 was synthesized by reacting the amino group of methyl anthranilate 1 with caffeic acid in the presence of PCl3. Cyclcondensation of 2 with hydrazine hydrate afforded the corresponding 2,3-dihydro-2-(3,4-dihydroxyphenyl) pyrazolo[5,1-b]quinazolin-9(1H)-one 3. The median lethal doses (LD50s) of compounds 2 and 3 in mice were 1,135 and 495 mg/kg b.w., respectively. The anti-inflammatory, reducing power, chelating activity on Fe2+, free radical-scavenging, and total antioxidant activities were more pronounced in compound 2 compared to compound 3. On the other hand, antipyretic activity was more pronounced in compound 3 compared to compound 2. Antioxidant activity of compounds 2 and 3 increased with increased concentrations. Total antioxidant activity of compounds 2, 3 and both standards decreased in the order of α-tocopherol > compound 2 > trolox > BHA > BHT > compound 3. Administration of compounds 2 and 3 orally to the rats at dose of 50, 100, and 150 mg/kg b.w., for 10 days showed non-significant changes in serum level of GOT, GPT, ALP, γ-GT, and LDH as compared with the control group. In addition, oral administration of the compound 2 at a concentration of 100 and 150 mg/kg b.w. and compound 3 at a concentration of 150 mg/kg b.w. daily to normal rats for 10 days showed a significant increase in liver GSH, GPx, GR, and GST activities and significant decrease in TBARS level. But, administration of diclofenac sodium (30 mg/kg b.w.) orally to the rats daily for 10 days to rats showed significant increase in serum SGOT, SGPT, ALP, γ-GT, and LDH and significant decrease in liver GSH, GPx, GR, and GST activities. These findings suggest that compounds 2 and 3 exhibited good antioxidant and anti-inflammatory activity and also showed effects on liver enzymes.

Medicinal chemistry matters – a call for discipline in our discipline

Medicinal chemistry makes a vital contribution to small molecule drug discovery, and the quality of it contributes directly to research effectiveness as well as to downstream costs, speed and survival in development. In recent years, the discipline of medicinal chemistry has evolved and witnessed many noteworthy contributions that propose and offer potential improvements to medicinal chemistry practice; however, the impact of these ideas is limited by their acceptance and deployment into every-day activity and, as a result, the quality of medicinal chemistry remains variable. For the good of the industry and the medicinal chemistry discipline, there is a need to move from retrospective learning to prospective control of medicinal chemistry practice to improve cost effectiveness, probability of success and survival rates.

The successful quest for oral factor Xa inhibitors; learnings for all of medicinal chemistry?

The medicinal chemistry of oral small molecule factor Xa inhibitors is discussed, highlighting key advances that led to clinical candidates and the first licensed medicines. Identification of neutral ligands for the primary specificity pocket was a key discovery; capitalised upon by structure based design and combinatorial methods to deliver many variations on the theme; but it was good medicinal chemistry practice, in the optimisation of physical properties, which ultimately delivered efficacious compounds with adequate oral exposure. As a retrospective appraisal, representative compounds were profiled using the more contemporary concepts of Ligand Efficiency and Property Forecast Indices; which gave clear indications of the value of these principles.

Ligand Efficiency Indices (LEIs): More than a Simple Efficiency Yardstick.

The concept of ligand efficiency and the usage of ligand efficiency values to assess the quality of fragments and compounds is becoming more accepted in the practice of medicinal chemistry. This is particularly true as it refers to the efficiency of ligands per unit size (i.e., binding affinity/number of non-hydrogen atoms or binding affinity/MW). The use of the Ligand Efficiency Indices (LEIs) as variables for a Cartesian mapping of chemico-biological space, the concept of AtlasCBS, has been presented in a recent publication with some initial drug-discovery applications. In this communication, we present additional applications of the concept in three domains of drug discovery: i) analyze and compare the content of databases: inhibitors vs. drugs; ii) polypharmacology; and iii) applications to Fragment-Based strategies. We suggest that the combined use of LEIs in a Cartesian representation of Chemico-Biological Space (AtlasCBS) could be a useful tool in various aspects of drug-discovery in the future.

Foreword: American Chemical Society Division of Medicinal Chemistry. Celebrating 100 Years of Excellence

ThisCentennial Issue of the Journal ofMedicinal Chemistry was conceived in order to commemorate the 100th anniversary of the Division of Medicinal Chemistry. The Journal is a fitting venue for this tribute. For the past 50 years, the Journal has been considered the flagship publication in our field anda rich repositoryof scientific advancement in the area of drug discovery. Thus, although the Journal and the Division have never been formally linked, they are inextricably united by a desire to advance the practice of medicinal chemistry. It is arguably fitting for me to write this foreword, since the formation of the Division of Medicinal Chemistry occurred less than amile fromwhere I now sit. The changes in the world, the field of medicinal chemistry, and the Division over the past 100 years have been nothing less than spectacular.

Book Review of The Practice of Medicinal Chemistry. Third Edition

Book Review of The Practice of Medicinal Chemistry. Third Edition

Neues Buch: The Practice of Medicinal Chemistry. Von Camille G. Wermuth.

Pharmazie in unserer ZeitVolume 34, Issue 5 p. 435-435 Neues Buch Neues Buch: The Practice of Medicinal Chemistry. Von Camille G. Wermuth. Holger Stark, Holger Stark FrankfurtSearch for more papers by this author Holger Stark, Holger Stark FrankfurtSearch for more papers by this author First published: 26 August 2005 https://doi.org/10.1002/pauz.200590094AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume34, Issue5September 2005Pages 435-435 RelatedInformation

The Practice of Medicinal Chemistry Edited by Camille Georges Wermuth. Academic Press, London. 2003. xv + 768 pp. 22 × 28 cm. ISBN 0-12-744481-5. $179.95.

ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTThe Practice of Medicinal Chemistry Edited by Camille Georges Wermuth. Academic Press, London. 2003. xv + 768 pp. 22 × 28 cm. ISBN 0-12-744481-5. $179.95.View Author Information Wyeth Research 401 North Middletown Road Pearl River, New York 10965Cite this: J. Med. Chem. 2004, 47, 16, 4109Publication Date (Web):June 15, 2004Publication History Published online15 June 2004Published inissue 1 July 2004https://doi.org/10.1021/jm0400956Copyright © 2004 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views221Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (13 KB) Get e-AlertsSUBJECTS:Medicinal chemistry Get e-Alerts

BREED: Generating novel inhibitors through hybridization of known ligands. Application to CDK2, p38, and HIV protease.

In this work we describe BREED, a method for the generation of novel inhibitors from structures of known ligands bound to a common target. The method is essentially an automation of the common medicinal chemistry practice of joining fragments of two known ligands to generate a new inhibitor. The ligand-bound target structures are overlaid, all overlapping bonds in all pairs of ligands are found, and the fragments on each side of each matching bond are swapped to generate the new molecules. Since the method is automated, it can be applied recursively to generate all possible combinations of known ligands. In an application of this method to HIV protease inhibitors and protein kinase inhibitors, hundreds of new molecular structures were generated. These included known inhibitor scaffolds not included in the initial set, entirely novel scaffolds, and novel substituents on known scaffolds. The method is fast, and since all of the ligand functional groups are known to bind the target in the precise position and orientation present in the novel ligand, the success rate of this method should be superior to more traditional de novo design techniques. In an era of increasingly high-throughput structural biology, such methods for high-throughput utilization of structural information will become increasingly valuable.

The Practice of Medicinal Chemistry

The Practice of Medicinal Chemistry Editor: Camille Georges Wermuth Published by Academic Press, 2003 624 pages. Price $174.95. ISBN 01274 4481 5 Published in 1996, the first edition of The Practice of Medicinal Chemistry edited by C. G. Wermuth was aimed at Medicinal Chemists who were very much at the beginning of their careers. The revised and expanded 2003 second edition builds on the success of the first edition but also captures the changes and future trends behind the science of new drug discovery and development. Beginning with an historical review of drug discovery and introductory chapters on the foundations and principles of medicinal chemistry, basic pharmacology and drug action, the first section very much sets the scene. Current and future strategies in the discovery of new leads are comprehensively discussed in Section 2, which includes chapters on combinatorial chemistry, natural product screening, in silico approaches, the contribution of molecular biology and the use and application of Internet-based resources. Sections 3, 4 and 5 focus on exploring structure–activity relationships and molecular modelling. While these sections are very much the domain of the traditional medicinal chemist, the material is presented in a format that does not daunt the reader but guides them through these complex principles and techniques practised in today's modern laboratories. Section 6 reflects the desire to design new drugs and prodrugs that, while maintaining appropriate safety and efficacy profiles, can be developed in a more efficient, timely and therefore less costly manner. Chapters describing the incorporation and optimization of drug-like properties from the outset, highlight the need for medicinal chemists to understand the basic principles of the associated disciplines of drug metabolism and pharmacokinetics. Section 7 tackles the perennial problem of aqueous solubility and offers the reader an understanding of solubility from a physicochemical perspective and discusses some of the techniques employed in improving solubility. These include incorporating salt formation and other structural solubilizing moieties, as well as using cyclodextrins and colloidal dispersion systems. Section 8 includes chapters on describing the entire process of drug development from discovery to product launch, a primer on drug (as opposed to chemical) nomenclature and drug manufacture, and a thought-provoking chapter on the information every chemist should know about patent protection. With over 750 pages containing 43 chapters from 55 authors, the eight broad topics covered in this book capture the whole spectrum of activities associated with both the theory and practice of rational drug design. The material is very much evidence based, authors drawing on personal and literature examples to illustrate the concepts and principles they expound. The book is well designed and reader friendly with comprehensive reference lists at the end of each chapter and a useful summary index. This is an impressive book suitable not only for Medicinal Chemists of all experience levels but for anyone working in the field of drug discovery. It would be a welcome addition to any drug discoverer's book shelf.

The Practice of Medicinal Chemistry, 2nd Ed Edited by C. G. Wermuth (University of Louis Pasteur). Academic Press, San Diego, CA. 2003. xv + 768 pp. 22 × 28.5 cm. $174.95. ISBN 0-12-744481-5.

ADVERTISEMENT RETURN TO ISSUEPREVBook ReviewNEXTThe Practice of Medicinal Chemistry, 2nd Ed Edited by C. G. Wermuth (University of Louis Pasteur). Academic Press, San Diego, CA. 2003. xv + 768 pp. 22 × 28.5 cm. $174.95. ISBN 0-12-744481-5.Matthias C. LuView Author Information University of Illinois at Chicago Chicago, IllinoisCite this: J. Nat. Prod. 2004, 67, 4, 738–739Publication Date (Web):March 10, 2004Publication History Published online10 March 2004Published inissue 1 April 2004https://doi.org/10.1021/np0307284Copyright © 2004 American Chemical Society and American Society of PharmacognosyRIGHTS & PERMISSIONSArticle Views173Altmetric-Citations3LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (41 KB) Get e-AlertsSUBJECTS:Amines,Drug discovery,Medicinal chemistry,Pharmaceuticals,Students Get e-Alerts

Use of combinatorial and multiple parallel synthesis methodologies for the development of anti-infective natural products

Abstract