SMALL MOLECULES SOLVING BIG PROBLEMS: PRESENT AND FUTURE OF DRUG DISCOVERY

The Drug development process has undergone a great change over the years. The way, from haphazard discovery of new natural products with a potent biological activity to a rational design of small molecule effective against a selected target, has been long and sprinkled with difficulties. The oldest drug development models are widely perceived as opaque and inefficient, with the cost of research and development continuing to rise even if the production of new drugs remains constant. The present paper, will give an overview of the principles, approaches, processes, and status of drug discovery today with an eye towards the past and the future.

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Fixing a broken drug development process

Journal of Commercial Biotechnology ◽

10.5912/jcb588 ◽

2013 ◽

Vol 19 (1) ◽

Cited By ~ 2

Author(s):

John Holland

Keyword(s):

Drug Discovery ◽

Development Process ◽

Pharmaceutical Research ◽

New Drugs ◽

Washington Dc ◽

Drug Development Process ◽

Drug Trials ◽

Low Levels ◽

The Cost ◽

The U.S

It costs about $1.2 billion to bring a single new drug to market in the U.S. today.[1] With a combination of high late-stage failure rates and the high cost of drug trials, the number of new drugs being approved by the FDA has flat-lined at historically low levels, falling from 53 in 1996 to just 19 in 2009.[2] If the cost of drug trials doesnâ€™t come down, we will see far fewer new drugs on pharmacy shelves. [1] Pharmaceutical Research and Manufacturers of America Profile 2009. Washington, DC: PhRMA. [2] Hughes B. 2009 Drug Approvals. Nature Reviews Drug Discovery 9, 89-92 (February 2010)

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Significant role of chemistry in drug development: a systematic journey from traditional to modern approaches with anti-HIV/AIDS drugs as examples

Current Pharmaceutical Design ◽

10.2174/1381612827666211102101617 ◽

2021 ◽

Vol 27 ◽

Author(s):

Madhu Yadav ◽

Ritika Srivastava ◽

Farha Naaz ◽

Rajesh Verma ◽

Ramendra K. Singh

Keyword(s):

Drug Discovery ◽

Drug Development ◽

Development Process ◽

New Drugs ◽

Computer Assisted ◽

Synthetic Chemistry ◽

Drug Development Process ◽

Drug Molecules ◽

Hiv Aids

Background: Traditionally, various plant extracts having interesting biological properties were the main source of new drugs. In the last 30 years, the role of chemistry in combination with new technologies, like various computational techniques in chemistry, has witnessed a major upsurge in drug discovery and targeted drug delivery. Objective: This article provides a succinct overview of recent techniques of chemistry that have a great impact on the drug development process in general and also against HIV/AIDS. It focuses on new methods employed for drug development with an emphasis on in silico studies, including identifying drug targets, especially the proteins associated with specific diseases. Methods: The rational drug development process starts with the identification of a drug target as the first phase, which helps in the computer-assisted design of new drug molecules. Synthetic chemistry has a major impact on the drug development process because it provides new molecules for future study. Natural products based semisynthesis or microwave assisted synthesis is also involved in developing newly designed drug molecules. Further, the role of analytical chemistry involves extraction, fractionation, isolation and characterization of newly synthesized molecules. Results: Chemistry plays a key role in drug discovery and delivery by natural process or with the help of synthetic nanoparticles or nanomedicines. So, nanochemistry is also deeply involved in the development of new drugs and their applications. Conclusion: The previous era of drug discovery was dominated only by chemistry, but the modern approaches involve a comprehensive knowledge of synthetic chemistry, medicinal chemistry, computational chemistry and the concerned biological phenomenon.

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Recent advances in the development of protein–protein interactions modulators: mechanisms and clinical trials

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-020-00315-3 ◽

2020 ◽

Vol 5 (1) ◽

Cited By ~ 1

Author(s):

Haiying Lu ◽

Qiaodan Zhou ◽

Jun He ◽

Zhongliang Jiang ◽

Cheng Peng ◽

...

Keyword(s):

Clinical Trials ◽

Drug Discovery ◽

Small Molecules ◽

Protein Interactions ◽

Clinical Studies ◽

New Drugs ◽

Protein Protein Interactions ◽

The Past ◽

Recent Advances ◽

Novel Drugs

Abstract Protein–protein interactions (PPIs) have pivotal roles in life processes. The studies showed that aberrant PPIs are associated with various diseases, including cancer, infectious diseases, and neurodegenerative diseases. Therefore, targeting PPIs is a direction in treating diseases and an essential strategy for the development of new drugs. In the past few decades, the modulation of PPIs has been recognized as one of the most challenging drug discovery tasks. In recent years, some PPIs modulators have entered clinical studies, some of which been approved for marketing, indicating that the modulators targeting PPIs have broad prospects. Here, we summarize the recent advances in PPIs modulators, including small molecules, peptides, and antibodies, hoping to provide some guidance to the design of novel drugs targeting PPIs in the future.

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Biomarkers and Surrogate Endpoints: How and When might They Impact Drug Development?

Disease Markers ◽

10.1155/2002/438745 ◽

2002 ◽

Vol 18 (2) ◽

pp. 83-90 ◽

Cited By ~ 15

Author(s):

Chetan D. Lathia

Keyword(s):

Decision Making ◽

Drug Development ◽

Development Process ◽

Surrogate Endpoints ◽

Pharmacokinetic Data ◽

Drug Development Process ◽

High Likelihood ◽

Molecular Pharmacology ◽

Toxicity Biomarkers ◽

The Cost

As the pharmaceutical industry starts developing novel molecules developed based on molecular biology principles and a better understanding of the human genome, it becomes increasingly important to develop early indicators of activity and/or toxicity. Biomarkers are measurements based on molecular pharmacology and/or pathophysiology of the disease being evaluated that may assist with decision-making in various phases of drug development. The utility of biomarkers in the development of drugs is described in this review. Additionally, the utility of pharmacokinetic data in drug development is described. Development of biomarkers may help reduce the cost of drug development by allowing key decisions earlier in the drug development process. Additionally, biomarkers may be used to select patients who have a high likelihood of benefit or they could be used by clinicians to evaluate the potential for efficacy after start of treatment.

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Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development

Processes ◽

10.3390/pr9010071 ◽

2020 ◽

Vol 9 (1) ◽

pp. 71

Author(s):

Outi M. H. Salo-Ahen ◽

Ida Alanko ◽

Rajendra Bhadane ◽

Alexandre M. J. J. Bonvin ◽

Rodrigo Vargas Honorato ◽

...

Keyword(s):

Molecular Dynamics ◽

Drug Discovery ◽

Drug Development ◽

Development Process ◽

Md Simulations ◽

Disordered Proteins ◽

Drug Development Process ◽

Formulation Development ◽

Pharmaceutical Development

Molecular dynamics (MD) simulations have become increasingly useful in the modern drug development process. In this review, we give a broad overview of the current application possibilities of MD in drug discovery and pharmaceutical development. Starting from the target validation step of the drug development process, we give several examples of how MD studies can give important insights into the dynamics and function of identified drug targets such as sirtuins, RAS proteins, or intrinsically disordered proteins. The role of MD in antibody design is also reviewed. In the lead discovery and lead optimization phases, MD facilitates the evaluation of the binding energetics and kinetics of the ligand-receptor interactions, therefore guiding the choice of the best candidate molecules for further development. The importance of considering the biological lipid bilayer environment in the MD simulations of membrane proteins is also discussed, using G-protein coupled receptors and ion channels as well as the drug-metabolizing cytochrome P450 enzymes as relevant examples. Lastly, we discuss the emerging role of MD simulations in facilitating the pharmaceutical formulation development of drugs and candidate drugs. Specifically, we look at how MD can be used in studying the crystalline and amorphous solids, the stability of amorphous drug or drug-polymer formulations, and drug solubility. Moreover, since nanoparticle drug formulations are of great interest in the field of drug delivery research, different applications of nano-particle simulations are also briefly summarized using multiple recent studies as examples. In the future, the role of MD simulations in facilitating the drug development process is likely to grow substantially with the increasing computer power and advancements in the development of force fields and enhanced MD methodologies.

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Ethics at Phase 0: Clarifying the Issues

The Journal of Law Medicine & Ethics ◽

10.1111/j.1748-720x.2007.00194.x ◽

2007 ◽

Vol 35 (4) ◽

pp. 727-733 ◽

Cited By ~ 21

Author(s):

Jonathan Kimmelman

Keyword(s):

Development Process ◽

Science Studies ◽

Critical Path ◽

Clinical Applications ◽

New Drugs ◽

Product Development Process ◽

Drug Development Process ◽

The Past ◽

Phase 0 ◽

Similar Vein

Many commentators have expressed concern that large investments in biomedical research over the past two decades have not been translated effectively into clinical applications. In its Critical Path Report, the Food and Drug Administration (FDA) characterized the problem as a “technological disconnect between discovery and the product development process,” and documented that the number of investigational new drugs (INDs) submitted to the agency had declined “significantly” since 2000. Along a similar vein, another study found that only five of 101 basic science studies showing significant therapeutic promise were successfully translated into clinical applications.This perceived translational lag is stimulating a shift toward human testing of study interventions earlier in the drug development process. One indication of this trend is a recent guidance encouraging sponsors to pursue human “exploratory” studies before embarking on phase I trials.

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Intelligent Drug Development

10.1093/oso/9780199974580.001.0001 ◽

2014 ◽

Author(s):

Michael Tansey

Keyword(s):

Clinical Trials ◽

Cost Effectiveness ◽

Drug Development ◽

Clinical Research ◽

Development Process ◽

Drug Development Process ◽

Individual Trial ◽

Specific Technology

Clinical research is heavily regulated and involves coordination of numerous pharmaceutical-related disciplines. Each individual trial involves contractual, regulatory, and ethics approval at each site and in each country. Clinical trials have become so complex and government requirements so stringent that researchers often approach trials too cautiously, convinced that the process is bound to be insurmountably complicated and riddled with roadblocks. A step back is needed, an objective examination of the drug development process as a whole, and recommendations made for streamlining the process at all stages. With Intelligent Drug Development, Michael Tansey systematically addresses the key elements that affect the quality, timeliness, and cost-effectiveness of the drug-development process, and identifies steps that can be adjusted and made more efficient. Tansey uses his own experiences conducting clinical trials to create a guide that provides flexible, adaptable ways of implementing the necessary processes of development. Moreover, the processes described in the book are not dependent either on a particular company structure or on any specific technology; thus, Tansey's approach can be implemented at any company, regardless of size. The book includes specific examples that illustrate some of the ways in which the principles can be applied, as well as suggestions for providing a better context in which the changes can be implemented. The protocols for drug development and clinical research have grown increasingly complex in recent years, making Intelligent Drug Development a needed examination of the pharmaceutical process.

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