Applications of molecular docking in natural products-based drug discovery

Natural products have a long history of use in the treatment of various diseases particularly in developing countries. The use of compounds of natural origin as lead compounds for the development of conventional drugs is widely recognised. Natural product-based drug discovery efforts in developing countries mostly involve the use of crude extracts in in-vitro and/or in-vivo assays. There are limited efforts at isolating active principles for structure elucidation studies. Studies that isolate pure secondary metabolites and characterize their structures have limited bioactivity evaluations. In conventional drug discovery programs, molecular docking serves as a useful tool for predicting interactions of small molecules with drug target(s) to guide synthesis decisions. Medicinal chemists use this tool to predict and synthesize compounds likely to have pharmacological activity and thus save time and cost for drug discovery. Efforts have been made to incorporate molecular docking techniques into natural products-based drug discovery. The objective of this review is to discuss molecular docking in natural product drug discovery programs with the goal of providing easy-to-understand information to help beginners interested in incorporating molecular docking in their research. This is expected to enhance natural product screening programs by predicting which phytochemicals are likely to show success, especially in new disease situations such as COVID-19. Applications in the repositioning of plants for emerging conditions are also discussed. © 2023

Discovery and Development Strategies for SARS-CoV-2 NSP3 Macrodomain Inhibitors.

The worldwide public health and socioeconomic consequences caused by the COVID-19 pandemic highlight the importance of increasing preparedness for viral disease outbreaks by providing rapid disease prevention and treatment strategies. The NSP3 macrodomain of coronaviruses including SARS-CoV-2 is among the viral protein repertoire that was identified as a potential target for the development of antiviral agents, due to its critical role in viral replication and consequent pathogenicity in the host. By combining virtual and biophysical screening efforts, we discovered several experimental small molecules and FDA-approved drugs as inhibitors of the NSP3 macrodomain. Analogue characterisation of the hit matter and crystallographic studies confirming binding modes, including that of the antibiotic compound aztreonam, to the active site of the macrodomain provide valuable structure-activity relationship information that support current approaches and open up new avenues for NSP3 macrodomain inhibitor development.

Computational approaches for drug repositioning and repurposing to combat SARS-CoV-2 infection

Drug repositioning (also referred to as drug repurposing) is the method of exploring novel therapeutic indications for Food and Drug Administration-approved clinically implemented drugs. The unique strategy of drug repositioning is used to boost the drug development process since drug discovery is an expensive, arduous, cumbersome, and high-risk procedure. Recently, several pharmaceutical firms have used the drug repositioning technique in their drug discovery and development programs to develop new medications based on the identification of new therapeutic targets. This technique is extremely effective, saves time, is comparatively economical, and has a low chance of failure. Developing appropriate treatment measures to inhibit the spread of Coronavirus disease-2019 (COVID-19) is currently a top priority. As a result, several studies were conducted to build novel therapeutic molecules using diverse strategies of drug repurposing to discover drug candidates against COVID-19 infection that can act as substantial inhibitors against virus particles. By implementing virtual screening of drug libraries, it is possible to identify potential drugs through drug repurposing. A molecular docking approach and calculation of binding free energy are used to estimate binding affinity and drug–receptor interactions. Drug-repurposing methodologies can be divided into three categories: target-oriented, drug-oriented, and disease-oriented, based on the gathered data about the various physicochemical, pharmacokinetic and pharmacological features of a drug candidate. Using computational methods such as homology modeling and molecular similarity, this methodology aids in determining the binding interaction of drug molecules with the target protein of the virus. In this book chapter, we explore a typical set of currently utilized computational techniques for identifying repurposable drug molecules for COVID-19, as well as their supporting databases. We also assess promising drugs anticipated by computational approaches to drugs currently being evaluated in clinical trials. Moreover, we also examine the takeaways from the evaluated research efforts, such as how to competently combine bioinformatics tools with experimental work and suggest a fully integrated drug-repurposing approach to combat the deadly COVID-19 infection. © 2022 Elsevier Inc. All rights reserved.

Introduction to the mini special issue on next generation drug discovery and development: rethinking translational pharmacology for accelerated drug development.

The coronavirus disease (COVID-19) pandemic further revealed the barriers to accelerated discovery and development of transformative medicines for life threatening diseases. To effectively and efficiently respond to unmet medical needs, efforts should be directed towards revolutionizing the predictive capability of non-clinical surrogates that inform drug discovery and development programs. I developed this mini special issue amidst the COVID-19 pandemic to evaluate recent advancements and opportunities for four main subthemes that support drug discovery and development including prediction of metabolic pathways, translational pharmacokinetic and pharmacodynamic studies, pharmacogenomics, and trends in bioanalysis. Scientific papers in these areas were covered by investigators from the International Society for the Study of Xenobiotics New Investigator Group and other investigators. Advancement in the predictive capability of in silico, in vitro, and in vivo models used to determine the absorption, distribution, metabolism, excretion, and toxicity profile of investigational drugs can help offset the cost of unexpected safety and/or efficacy issues during clinical studies. Likewise, extensive application of pharmacogenomics in drug development and clinical care can help direct therapeutic benefits to the appropriate patient population with the overall goal of accelerating drug development and mitigating failed drug cost. Finally, I hope that the scientific contributions in this mini special issue will stimulate practical advancements across all aspects of basic science research that support drug discovery and development to help unlock the door to the next generation of drug discovery and development that features reduced failure rates and accelerated development.

A painful lesson from the COVID-19 pandemic: the need for broad-spectrum, host-directed antivirals.

While the COVID-19 pandemic has spurred intense research and collaborative discovery worldwide, the development of a safe, effective, and targeted antiviral from the ground up is time intensive. Therefore, most antiviral discovery efforts are focused on the re-purposing of clinical stage or approved drugs. While emerging data on drugs undergoing COVID-19 repurpose are intriguing, there is an undeniable need to develop broad-spectrum antivirals to prevent future viral pandemics of unknown origin. The ideal drug to curtail rapid viral spread would be a broad-acting agent with activity against a wide range of viruses. Such a drug would work by modulating host-proteins that are often shared by multiple virus families thereby enabling preemptive drug development and therefore rapid deployment at the onset of an outbreak. Targeting host-pathways and cellular proteins that are hijacked by viruses can potentially offer broad-spectrum targets for the development of future antiviral drugs. Such host-directed antivirals are also likely to offer a higher barrier to the development and selection of drug resistant mutations. Given that most approved antivirals do not target host-proteins, we reinforce the need for the development of such antivirals that can be used in pre- and post-exposure populations.

Discovery and development of safe-in-man broad-spectrum antiviral agents.

Viral diseases are one of the leading causes of morbidity and mortality in the world. Virus-specific vaccines and antiviral drugs are the most powerful tools to combat viral diseases. However, broad-spectrum antiviral agents (BSAAs, i.e. compounds targeting viruses belonging to two or more viral families) could provide additional protection of the general population from emerging and re-emerging viral diseases, reinforcing the arsenal of available antiviral options. Here, we review discovery and development of BSAAs and summarize the information on 120 safe-in-man agents in a freely accessible database (https://drugvirus.info/). Future and ongoing pre-clinical and clinical studies will increase the number of BSAAs, expand the spectrum of their indications, and identify drug combinations for treatment of emerging and re-emerging viral infections as well as co-infections.