The In Silico Drug Discovery Toolbox: Applications in Lead Discovery and Optimization

2019 ◽  
Vol 26 (21) ◽  
pp. 3838-3873 ◽  
Author(s):  
Agostino Bruno ◽  
Gabriele Costantino ◽  
Luca Sartori ◽  
Marco Radi
Keyword(s):  
Drug Discovery ◽  
Success Rate ◽  
In Silico ◽  
Development Program ◽  
Lead Optimization ◽  
New Drugs ◽  
Safety Issues ◽  
New Drug ◽  
Discovery Pipeline ◽  
In Silico Tools

Background: Discovery and development of a new drug is a long lasting and expensive journey that takes around 20 years from starting idea to approval and marketing of new medication. Despite R&D expenditures have been constantly increasing in the last few years, the number of new drugs introduced into market has been steadily declining. This is mainly due to preclinical and clinical safety issues, which still represent about 40% of drug discontinuation. To cope with this issue, a number of in silico techniques are currently being used for an early stage evaluation/prediction of potential safety issues, allowing to increase the drug-discovery success rate and reduce costs associated with the development of a new drug. Methods: In the present review, we will analyse the early steps of the drug-discovery pipeline, describing the sequence of steps from disease selection to lead optimization and focusing on the most common in silico tools used to assess attrition risks and build a mitigation plan. Results: A comprehensive list of widely used in silico tools, databases, and public initiatives that can be effectively implemented and used in the drug discovery pipeline has been provided. A few examples of how these tools can be problem-solving and how they may increase the success rate of a drug discovery and development program have been also provided. Finally, selected examples where the application of in silico tools had effectively contributed to the development of marketed drugs or clinical candidates will be given. Conclusion: The in silico toolbox finds great application in every step of early drug discovery: (i) target identification and validation; (ii) hit identification; (iii) hit-to-lead; and (iv) lead optimization. Each of these steps has been described in details, providing a useful overview on the role played by in silico tools in the decision-making process to speed-up the discovery of new drugs.

scholarly journals Drug Repurposing: A Paradigm Shift in Drug Discovery

2020 ◽  
Vol 5 (04) ◽  
pp. 60-68
Author(s):  
Saravanan Jayaram ◽  
Emdormi Rymbai ◽  
Deepa Sugumar ◽  
Divakar Selvaraj
Keyword(s):  
Drug Discovery ◽  
Success Rate ◽  
Chemical Structure ◽  
Target Identification ◽  
Drug Repurposing ◽  
New Drugs ◽  
Attractive Option ◽  
Traditional Drug ◽  
Repurposed Drugs

The traditional methods of drug discovery and drug development are a tedious, complex, and costly process. Target identification, target validation; lead identification; and lead optimization are a lengthy and unreliable process that further complicates the discovery of new drugs. A study of more than 15 years reports that the success rate in the discovery of new drugs in the fields of ophthalmology, cardiovascular, infectious disease, and oncology to be 32.6%, 25.5%, 25.2% and 3.4%, respectively. A tedious and costly process coupled with a very low success rate makes the traditional drug discovery a less attractive option. Therefore, an alternative to traditional drug discovery is drug repurposing, a process in which already existing drugs are repurposed for conditions other than which were originally intended. Typical examples of repurposed drugs are thalidomide, sildenafil, memantine, mirtazapine, mifepristone, etc. In recent times, several databases have been developed to hasten drug repurposing based on the side effect profile, the similarity of chemical structure, and target site. This work reviews the pivotal role of drug repurposing in drug discovery and the databases currently available for drug repurposing.

Proposed Standards and Regulatory Mechanisms for New Homeopathic Drug Development

2021 ◽  
Vol 34 (04) ◽  
pp. 283-290
Author(s):  
Gitanjali Talele ◽  
Rajesh Shah
Keyword(s):  
Drug Discovery ◽  
Drug Development ◽  
Regulatory Mechanism ◽  
New Drugs ◽  
Regulatory Mechanisms ◽  
Regulatory Body ◽  
Market Authorisation ◽  
New Drug ◽  
Homeopathic Drug ◽  
Basic Proposition

Abstract Introduction Researchers working with new insights and new targets in new drug discovery in the homeopathy space observe that the path of drug-development and market authorisation has been less travelled and the pathway is not yet well-mapped. The need of the time is to define clear guidelines and regulatory mechanisms to facilitate the process of new drug discovery. Overview The article is about the proposed methods for identifying the new homeopathic substances for therapeutic use. An overview of the current regulations for drug development in India is discussed in this article. Method of new drug development in homeopathy, standards and regulatory mechanism for approval of new drugs are proposed with few illustrations and references. An introductory plan, based on the perspective and experience of researcher, practitioner, academician and inventor for drug discovery is proposed. Discussion An urgent need for setting up the guidelines for new drug discovery has been identified and a basic proposition is made for the same, suggesting practical, pragmatic and achievable measures, and independent regulatory body to encourage drug development and research.

scholarly journals In silico Strategies to Support Fragment-to-Lead Optimization in Drug Discovery

2020 ◽  
Vol 8 ◽  
Author(s):  
Lauro Ribeiro de Souza Neto ◽  
José Teófilo Moreira-Filho ◽  
Bruno Junior Neves ◽  
Rocío Lucía Beatriz Riveros Maidana ◽  
Ana Carolina Ramos Guimarães ◽  
...  
Keyword(s):  
Drug Discovery ◽  
In Silico ◽  
Lead Optimization

scholarly journals Drug Repurposing (DR): An Emerging Approach in Drug Discovery

2020 ◽  
Author(s):  
Mithun Rudrapal ◽  
Shubham J. Khairnar ◽  
Anil G. Jadhav
Keyword(s):  
Drug Discovery ◽  
De Novo ◽  
Drug Repositioning ◽  
Development Program ◽  
Drug Repurposing ◽  
New Drugs ◽  
Time Saving ◽  
Biological Targets ◽  
Drug Molecules ◽  
Traditional Drug

Drug repurposing (DR) (also known as drug repositioning) is a process of identifying new therapeutic use(s) for old/existing/available drugs. It is an effective strategy in discovering or developing drug molecules with new pharmacological/therapeutic indications. In recent years, many pharmaceutical companies are developing new drugs with the discovery of novel biological targets by applying the drug repositioning strategy in drug discovery and development program. This strategy is highly efficient, time saving, low-cost and minimum risk of failure. It maximizes the therapeutic value of a drug and consequently increases the success rate. Thus, drug repositioning is an effective alternative approach to traditional drug discovery process. Finding new molecular entities (NME) by traditional or de novo approach of drug discovery is a lengthy, time consuming and expensive venture. Drug repositioning utilizes the combined efforts of activity-based or experimental and in silico-based or computational approaches to develop/identify the new uses of drug molecules on a rational basis. It is, therefore, believed to be an emerging strategy where existing medicines, having already been tested safe in humans, are redirected based on a valid target molecule to combat particularly, rare, difficult-to-treat diseases and neglected diseases.

NERDD: a web portal providing access to in silico tools for drug discovery

2019 ◽  
Author(s):  
Conrad Stork ◽  
Gerd Embruch ◽  
Martin Šícho ◽  
Christina de Bruyn Kops ◽  
Ya Chen ◽  
...  
Keyword(s):  
Drug Discovery ◽  
In Silico ◽  
Organic Molecules ◽  
Web Portal ◽  
Small Organic Molecules ◽  
Biological Assays ◽  
Software Packages ◽  
Large Compound ◽  
Local Installation ◽  
In Silico Tools

Abstract Summary The New E-Resource for Drug Discovery (NERDD) is a quickly expanding web portal focused on the provision of peer-reviewed in silico tools for drug discovery. NERDD currently hosts tools for predicting the sites of metabolism (FAME) and metabolites (GLORY) of small organic molecules, for flagging compounds that are likely to interfere with biological assays (Hit Dexter), and for identifying natural products and natural product derivatives in large compound collections (NP-Scout). Several additional models and components are currently in development. Availability and implementation The NERDD web server is available at https://nerdd.zbh.uni-hamburg.de. Most tools are also available as software packages for local installation. Contact [email protected]

scholarly journals Repurposing – second life for drugs

Pharmacia ◽  
2022 ◽  
Vol 69 (1) ◽  
pp. 51-59
Author(s):  
Porkodi Ayyar ◽  
Umamaheswari Subramanian
Keyword(s):  
Drug Discovery ◽  
Second Life ◽  
Drug Repurposing ◽  
New Drugs ◽  
Protein Targets ◽  
Medical Needs ◽  
New Drug ◽  
Patent Expiry ◽  
Traditional Drug ◽  
Increasing Demand

Drug repurposing refers to finding new indications for existing drugs. The paradigm shift from traditional drug discovery to drug repurposing is driven by the fact that new drug pipelines are getting dried up because of mounting Research & Development (R&D) costs, long timeline for new drug development, low success rate for new molecular entities, regulatory hurdles coupled with revenue loss from patent expiry and competition from generics. Anaemic drug pipelines along with increasing demand for newer effective, cheaper, safer drugs and unmet medical needs call for new strategies of drug discovery and, drug repurposing seems to be a promising avenue for such endeavours. Drug repurposing strategies have progressed over years from simple serendipitous observations to more complex computational methods in parallel with our ever-growing knowledge on drugs, diseases, protein targets and signalling pathways but still the knowledge is far from complete. Repurposed drugs too have to face many obstacles, although lesser than new drugs, before being successful.

In-silico ADME Studies for New Drug Discovery: From Chemical Compounds to Chinese Herbal Medicines

2017 ◽  
Vol 18 (6) ◽  
Author(s):  
Guojun Yan ◽  
Xiaobing Wang ◽  
Zhou Chen ◽  
Xianhui Wu ◽  
Jinhuo Pan ◽  
...  
Keyword(s):  
Drug Discovery ◽  
In Silico ◽  
Herbal Medicines ◽  
Chemical Compounds ◽  
Chinese Herbal Medicines ◽  
Chinese Herbal ◽  
New Drug

scholarly journals The Success Rate of New Drug Development in Clinical Trials: Crohn’s Disease

2010 ◽  
Vol 13 (2) ◽  
pp. 191 ◽  
Author(s):  
Jayson Lee Parker ◽  
Jillian Clare Kohler
Keyword(s):  
Clinical Trial ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Drug Development ◽  
Success Rate ◽  
Small Molecule ◽  
New Drugs ◽  
Press Releases ◽  
New Drug ◽  
Trial Testing

Purpose. To determine the risk of drug failure during clinical trial testing in Crohn’s disease and determine what steps can be taken to improve outcomes. This is the first study to quantify such risk for a single disease. Methods. Moderate to severe Crohn’s disease was investigated by reviewing press releases from 1998 to June 2008. Clinical trial failure causes were classified as commercial or clinical and compared with industry expectations. The risk of failure was also reviewed based on whether the compound was a small molecule drug or a biologic. Lastly, the role of the sponsor was examined, in determining whether the size of the firm involved in a drug program was predictive of the outcome of the study. Results. More than a120 press releases were reviewed yielding 37 drugs that met our search criteria. The cumulative success rate for drug development in Crohn’s disease is 19%, from start to finish of clinical trial testing. New drug approvals are dominated by protein based therapeutics in this indication. Commercial and clinical failures both contributed substantially to the failure rates of new drugs. Phase I clinical testing appeared to offer little risk mitigation with pass rates at 95%. Conclusion. Funding intended to advance Crohn’s disease must take into account the disease specific historical failure rate of drug development in forecasting any reasonable expectation of producing new therapies. As it currently stands, one in five drugs will be successfully approved that enter clinical trial testing in this indication. To manage this risk continued development of biologics over small molecule drugs may be warranted in this disease.

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