RSC Advances Blog

We are very pleased to introduce Rajendra Joshi and the team of authors of the paper ‘Remdesivir-bound and ligand-free simulations reveal the probable mechanism of inhibiting the RNA dependent RNA polymerase of severe acute respiratory syndrome coronavirus 2‘. Their article has been very well received and handpicked by our reviewers and handling editors as one of our HOT articles. The team told us more about the work that went into this article and what they hope to achieve in the future. You can find out more about the authors and their article below and find more HOT articles in our online collection.

About Dr Rajendra Joshi

Dr. Rajendra Joshi received his Ph.D. in Biochemistry from National Chemical Laboratory, Pune, India in 1994. He has been associated with the area of Biotechnology & Bioinformatics for the about 28 years. He is presently serving as a Senior Director and Head of the Department, High Performance Computing-Medical and Bioinformatics Applications Group, at C-DAC, Pune.

His major area of expertise, is in the use of high performance parallel computers for biological research. His unique strength is in the form of good knowledge of biology and parallel computing. His main research interests include, molecular dynamics simulations of nucleic acids & proteins, genome sequence analysis, metabolic pathways and development of Problem Solving Environments. He has around 66 publications in internationally peer reviewed journals.

Could you briefly explain the focus of your article to the non-specialist (in one or two sentences only) and why it is of current interest?
Remdesivir, the emergency drug approved for treating COVID-19 patients helps in blocking the multiplication of SARS-CoV-2 virus. The action of this drug on the viral protein RNA dependent RNA polymerase was mimicked using computational methods, namely, molecular docking and molecular dynamics simulations.

How big an impact could your results potentially have?
The predicted mechanism of action of the drug, remdesivir, on the viral protein of SARS-CoV-2 would help in designing inhibitor molecules against the viruses. The drug target protein is the one, which is observed to be the most conserved among the coronavirus family. Statistically significant results produced through computational drug repurposing methods, add to the prediction accuracy of the drug-target interactions that are of major interest to develop therapeutics.

Could you explain the motivation behind this study?
The need to find the best solution against the global pandemic was the biggest motivation behind this study. This work was performed in the month of May 2020 and during that time, remdesivir, was being considered as one of the best solutions to treat the COVID-19 patients until the designing of the vaccine. Understanding the mechanism adopted by remdesivir would add to the information on the drug-action mechanism. This would be of importance to the experimental and pharmaceutical labs in the process of drug development.

In your opinion, what are the key design considerations for your study?
The key design considerations of our study was to mimic the RNA dependent RNA polymerase inhibition by remdesivir. Trying to understand the structure of RdRP and designing the best fit molecule which can inhibit the drug target with more potency. Being a part of, one of the High Performance Computing (HPC) groups in India, the entire computational study was designed around making the best use of the HPC technologies available to us.

Which part of the work towards this paper proved to be most challenging?
The research work involved many challenges since we had to design simulation systems with limited and evolving structural information of this virus. The major challenge being performing the computational drug repurposing studies in order to accelerate this research. In addition, the analytics involving statistical techniques for the identification of crucial residues and subdomains of the viral protein RNA dependent RNA polymerase also proved to be challenging.

What aspect of your work are you most excited about at the moment?
The mechanism of action and crucial interacting residues predicted through the computational methods in our present study were observed to match the experimental structures that are being elucidated for the RNA dependent RNA polymerase of the SARS-CoV-2.

What is the next step? What work is planned?
The work in this article dealt with remdesivir action in inhibiting the RNA dependent RNA polymerase of SARS-CoV-2. Besides remdesivir, other nucleotide analogues are also known to inhibit RdRP from the other coronaviruses. Hence, we have planned to study the inhibitory mechanism of other nucleotide/nucleoside analogues namely, favipiravir, galidesivir, lamivudine, ribavirin and sofosbuvir in their active metabolite form. This work is currently being targeted using molecular docking and molecular dynamics simulations. We have planned to understand the conformational changes that the RdRP undergoes on binding to natural nucleotides and their analogues. This information may help in designing of better nucleotide analogues.

One more aspect we plan to study is the role of phytochemicals from medicinal plants that are known to be used as a treatment for respiratory ailments. All the data obtained through simulations has been thoroughly sampled and analyzed using statistically significant methods, such as, principal component analysis and Markov state modeling analysis.

Remdesivir-bound and ligand-free simulations reveal the probable mechanism of inhibiting the RNA dependent RNA polymerase of severe acute respiratory syndrome coronavirus 2
Shruti Koulgi, Vinod Jani, Mallikarjunachari V. N. Uppuladinne, Uddhavesh Sonavane and Rajendra Joshi
RSC Adv., 2020,10, 26792-26803
DOI: 10.1039/D0RA04743K, Paper

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We are very pleased to introduce Marisa G. Santibáñez-Morán (first author), José Medina-Franco (corresponding author) and the team behind the paper ‘Consensus virtual screening of dark chemical matter and food chemicals uncover potential inhibitors of SARS-CoV-2 main protease‘. Their article has been very well received and handpicked by our reviewers and handling editors as one of our HOT articles. The team told us more about the work that went into this article and what they hope to achieve in the future. You can find out more about the authors and their research at DIFACQUIM, Computer-aided drug-design at UNAM, and find more HOT articles in our online collection.

Could you briefly explain the focus of your article to the non-specialist (in one or two sentences only) and why it is of current interest?
Our article looks for molecules in food chemicals or dark chemical matter (molecules that had not shown activity in 100 or more high-throughput screening assays) that are prospective inhibitors of the SARS-CoV-2 Main protease.

How big an impact could your results potentially have?
It could point to SARS-CoV-2 inhibitors that might otherwise have been overlooked. We would be glad if other research groups will be interested in the computational hits we made publicly available and further analyzed them in experimental assays.

Could you explain the motivation behind this study?
COVID-19 is currently affecting all aspects of human life. Our research group works on computer-aided drug design, and we had previously worked on drug repurposing. We felt that we could and should contribute to the collaborative efforts of scientists from all around the world.

In your opinion, what are the key design considerations for your study?
One was the selection of the molecular libraries where we looked for potential inhibitors. These comprise compounds that recent studies on SARS-CoV-2 have analyzed on a limited basis. Additionally, a large number of these molecules are ready to be tested in experimental assays. Moreover, there are currently numerous papers that reported favorable molecular docking results. However, selecting compounds that would have satisfactory potency and biopharmaceutical results in experimental settings is not trivial. Therefore, we ranked the compounds considering positive results by two molecular docking programs, Machine learning predictions, commercial availability, and ADMETox properties.

Which part of the work towards this paper proved to be most challenging?
First, to select a target and molecular queries for the structural similarity analyses. The latter should include structurally diverse and promising compounds. Another challenge was to create a classification method that helps us select compounds with better possibilities for drug development.

What aspect of your work are you most excited about at the moment?
I am excited about the possibility of finding supporting information about the activity of food chemicals against SARS-CoV-2. I believe that this could result in the development of nutraceuticals with inhibitory activity against the SARS-CoV-2 virus.

What is the next step? What work is planned?
We are waiting for the experimental results of 3 compounds that are being tested by our collaborators in North Carolina. We are also working on another manuscript that explores a broader region of the chemical space. And we hope that we could form new collaborations with RSC Advances readers.

Consensus virtual screening of dark chemical matter and food chemicals uncover potential inhibitors of SARS-CoV-2 main protease
Marisa G. Santibáñez-Morán, Edgar López-López, Fernando D. Prieto-Martínez, Norberto Sánchez-Cruz and José L. Medina-Franco
RSC Adv., 2020,10, 25089-25099
DOI: 10.1039/D0RA04922K, Paper

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We are very pleased to introduce Pavel Bobal, Jan Otevrel and David Svestka, the authors of the paper ‘One-pot method for the synthesis of 1-aryl-2-aminoalkanol derivatives from the corresponding amides or nitriles‘. Their article has been very well received and handpicked by our reviewers and handling editors as one of our HOT articles.  The team told us more about the work that went into this article and what they hope to achieve in the future. You can find out more about the authors and their article below and find more HOT articles in our online collection.

Meet the Authors

	Pavel Bobal studied organic chemistry at Slovak Technical University, Bratislava, Slovakia, where he received his doctoral degree in 1996. He spent 3 years between 1995 and 1998 as a postdoc at the University of Neuchatel, Switzerland (Prof. Neier) and additional 3 years at the University of Nevada, Reno, USA (Prof. Lightner). From 2001 to 2009 he worked in the pharmaceutical industry (R&D). In 2009 he became an assistant professor and then in 2019 an associate professor at Faculty of Pharmacy, UVPS Brno, Czech Republic. Since 2020 this faculty has been reestablished as a part of Masaryk University, Brno, Czech Republic.
	Jan Otevrel was a former Ph.D. student of Pavel Bobal, he received his doctoral degree in 2017 and then became an assistant professor at the same university. During his Ph.D. he spent 3 months at Justus Liebig University, Giessen, Germany (Prof. Hrdina) and he will soon (this year) start a postdoc position at Johannes Kepler University, Linz, Austria (Prof. Waser). He has discovered and co-developed the process published in the current study.
	David Svestka received his master’s degree in 2019 at UVPS Brno, Czech Republic. He is currently a Ph.D. student in the Pavel Bobal’s laboratory and participated in the development of the present method.

Could you briefly explain the focus of your article to the non-specialist (in one or two sentences only) and why it is of current interest?
Our paper describes a new method for synthesis of vicinal amino alcohols from the respective amides or nitriles by a simple set of reaction conditions. Amino alcohols are compounds of high interest in many branches of chemistry.

How big an impact could your results potentially have?
It is always hard to predict feedback of the scientific article. However, from our perspective, we would be glad if the developed process will find place in syntheses of vicinal amino alcohols conducted at research laboratories and if the readers of RSC Advances will appreciate efforts which we have invested in this paper.

Could you explain the motivation behind this study?
Due to our continuous interest in the organocatalyzed aldol-type reactions, we have been exploring syntheses of numerous chiral auxiliaries for the catalyst design and screening. These long-term endeavor paved a way for our current unexpected discovery.

In your opinion, what are the key design considerations for your study?
The key consideration in this study is to use an old and well-known reagent in a new context to reveal the novel and yet unexplored reactivity.

Which part of the work towards this paper proved to be most challenging?
The methodological articles in organic synthesis usually share the common structure such as the optimization section, determination of the substrate scope, and a relevant synthetic application of the method. Thus from the initial interesting observation, it is often quite a long journey towards the good scientific paper. Honestly, one of the most challenging parts of the above article was to establish a plausible mechanism of the reaction and to support it with enough evidence.

What aspect of your work are you most excited about at the moment?
One of the most exciting moments of this discovery was to figure out that benzylic oxidation can occur even under reduction conditions, which is somewhat counter-intuitive. Indeed, sodium bis(methoxyethoxy)aluminum hydride gave us a great lecture that more than 50 years old and almost comprehensively explored reagent is still able to surprise.

What is the next step? What work is planned?
We will continue with our work in organic synthesis and medicinal chemistry and we will look forward to the new and especially the unexpected chemical discoveries.

One-pot method for the synthesis of 1-aryl-2-aminoalkanol derivatives from the corresponding amides or nitriles
Jan Otevrel, David Svestka and Pavel Bobal
RSC Adv., 2020,10, 25029-25045
DOI: 10.1039/D0RA04359A, Paper

Submit to RSC Advances today! Check out our author guidelines for information on our article types or find out more about the advantages of publishing in a Royal Society of Chemistry journal.

Keep up to date with our latest HOT articles, Reviews, Collections & more by following us on Twitter. You can also keep informed by signing up to our E-Alerts.