Key factors in the rising cost of new drug discovery and development

Dickson, Michael; Gagnon, Jean Paul

doi:10.1038/nrd1382

Cited by 517 publications

(357 citation statements)

References 27 publications

Supporting

Mentioning

346

Contrasting

Unclassified

Order By: Relevance

“…If adverse effects are not life-threatening and considered minor and rare, and if the treatment attains its clinical purpose, the results of all clinical stages are submitted as a New Drug Application to the FDA [9,28,36] Male reproductive function concerns during the drug development phase…”

Section: Discussionmentioning

confidence: 99%

Assessing Male Reproductive Toxicity during Drug Development

Sousa¹,

Ferreira²,

Rabaça³

et al. 2017

Andrology

View full text Add to dashboard Cite

Medical drug development is a crucial research field that attends to population healthcare needs, comprising several preclinical and clinical steps before the approval of a new compound. One major cause of pharmaceutical drug development failure is toxicity, especially in respect to kidney and liver. Nonetheless, the male reproductive system may also be a target for drug toxicity. Although the reproductive health is an important component of the person life, reproductive toxicology testing is rarely performed, both in pre-clinical and clinical trial phases. As reproductive and testicular toxicity is found at a low incidence during the early stages of drug development, companies devote the majority of research investments to more frequent areas of toxic occurrence. It is here suggested the inclusion of comprehensive studies and more precise methods to uncover the toxic reproductive effects and causes when developing new pharmacological drugs.

show abstract

Section: Discussionmentioning

confidence: 99%

Assessing Male Reproductive Toxicity during Drug Development

Sousa¹,

Ferreira²,

Rabaça³

et al. 2017

Andrology

View full text Add to dashboard Cite

show abstract

“…It is an abstract description of molecular features, which are necessary for molecular recognition of a ligand by a biological macromolecule, furthermore the pharmacophore shows what are the functional important groups inside ligand for protein interactions and its features [5].…”

Section: Pharmacophore Modeling and Virtual Computational Screeningmentioning

confidence: 99%

Pharmacophore modeling, virtual computational screening and biological evaluation studies

Dotolo

Facchiano

2017

Preprint

View full text Add to dashboard Cite

Drug discovery process plays an important role in identifying new investigational drug-likes and developing new potential inhibitors related to a determinate target, in biopharmaceutical field [1]. An alternative promising and efficient used to identify new active substances is Pharmacophore modeling method.We defined a new computational strategy protocol characterized by the use of bioinformatics online tools and by the application of locally installed tools, for lead candidates generation-optimization able to reduce the cycle time and cost of this process and to promote the next steps of study [2].Hence, we have tried to apply this new computational procedure, in a more detailed screening, of small bioactive molecules, searching and identifying new candidates as "lead compounds", potentially able to inhibit biological target AKT1 human protein and its related molecular mechanisms [3].The workflow executed in our work has been characterized by a multi-step design, which concerns different topics: search in PDB database of a model structure for AKT1, pharmacophore modeling and virtual computational screening, biological evaluation divided in two parts (molecular validation of selected compounds and study of physical-chemical properties related to pharmacokinetic/pharmacodynamics prediction models). All these step have been performed through PHARMIT (http://pharmit.csb.pitt.edu) and Discovery Studio 4.5 platform.We selected the PDB structure 3O96 as the reference complex (protein-ligand), and we analyzed it by means of PHARMIT and Discovery Studio, to generate four different "pharmacophore models" with four different list of natural compounds.It is performed a thorough screening of compounds applying several filters, to find some good candidates as possible natural AKT1 allosteric inhibitors.The compounds that match a well-defined pharmacophore have been analyzed through direct molecular docking, for selecting only the best candidates and studying the protein-ligand interactions. Selected compounds have been investigated in more details, to trace their origin, by their chemical-physical properties.This information can help us to predict some plausible enzyme-catalyzed reaction pathways, through PathPred web-server and KEGG compound database, in order to highlight the most important reactions for biosynthesis of compounds and obtain PharmacoKinetics/PharmacoDynamics (PK/PD) models, to investigate the ADMET properties of these lead compounds and to study their behavior in some biological systems, for the next experimental assays.This new computational strategy has been very efficient in showing what could be good "lead compounds" and potential natural inhibitors of AKT1 and PI3K/AKT1 signaling cascade. Therefore, the next steps could be the experimental analysis of pharmacokinetics-pharmacodynamics and toxicity properties "in vitro/in vivo", in order to evaluate the results obtained "in silico".PeerJ Preprints | https://doi.org/10.7287/peerj.preprints.2721v1 | CC BY 4.0 Open Access |

show abstract

“…membrânico, transmembrânico ou intracelular, bem como o tipo de intervenção terapêutica que se pretenda realizar, e.g. inibição enzimática, antagonista ou agonista de biorreceptores 27 . A escolha da estratégia de planejamento estrutural a ser adotada para o desenho molecular do novo ligante dependerá do nível de conhecimento estrutural do alvo terapêutico eleito.…”

Section: Figura 6 Estratégias Empregadas Na Identificação De Um Novounclassified

A questão da inovação em fármacos no Brasil: proposta de criação do programa nacional de fármacos (Pronfar)

Barreiro¹,

Fraga²

2005

Quím. Nova

View full text Add to dashboard Cite

Key factors in the rising cost of new drug discovery and development

Cited by 517 publications

References 27 publications

Assessing Male Reproductive Toxicity during Drug Development

Assessing Male Reproductive Toxicity during Drug Development

Pharmacophore modeling, virtual computational screening and biological evaluation studies

A questão da inovação em fármacos no Brasil: proposta de criação do programa nacional de fármacos (Pronfar)

Contact Info

Product

Resources

About