Frontiers in Drug Design and Discovery

A drug takes many years to develop and reach the market using the conventional drug discovery procedure. Computer-aided drug design (CADD) is an emerging technology that accelerates the process of drug discovery and minimizes the total expenditure associated with labour and resources. In the current scenario, the computational aided drug design (CADD) techniques play a significant role in the design and development of lead molecules for the treatment of various lethal pathological conditions. The prediction of the tertiary structure of a protein is a big concern in drug design and discovery. A typical drug discovery procedure starts with the tertiary structure of a protein. At present, a total of 184,407 protein structures are available in the protein data bank, which are determinedusing experimental methods. However, the procedures are difficult and time-consuming. A more advanced technique has been developed for the prediction of the 3D structure of a protein using a computational method. This technique has played a vital role in drug discovery. It has not only facilitated but also hastened the process of drug discovery. The method is named homology modeling since it involves the building of a protein model based on its homology to similar evolutionary proteins. The method is based on the fact that evolutionary related proteins have similar structures. In homology modelling, the 3D structure of a protein is derived from its primary sequence based on its similarity to the existing protein templates. There are many computational tools for homology modelling such as Modeller, Swiss model, Composer, 3D-JIGSAW, etc. The proposed book chapter will cover the introduction to homology modelling, step-by-step guide to building a protein model, various challenges and how to refine and validate the model, different algorithms related to sequence alignment, similarity search, and the applications of homology modelling in drug design and discovery. The chapter would be very fruitful to the readers to get insights into protein modelling, which will facilitate their research activities. It will be of great application in various disciplines,such as bioinformatics, physics, structural biology, and molecular biology. The content of the chapter will cover various research papers, review papers, and corresponding reference books.

Parasites and infectious agents are responsible for neglected tropical diseases (NTDs) that affect many countries worldwide. At least one NTD is found 149 countries, mostly in low-income countries with poor sanitation, and it impacts over a billion people. According to the World Health Organization, trypanosomiasis is a group of protozoan infections that cause Chagas disease (Trypanosoma cruzi), Human African Trypanosomiasis (sleeping sickness - Trypanosoma brucei rhodesiense or Trypanosoma brucei gambiense), and Leishmaniasis (Leishmania spp. - Trypanosomatidae family), which are all considered NTDs. It is estimated that approximately 500,000 deaths from NTD infections occur annually worldwide. Despite the many cases associated with NTDs, treatments for most of these diseases are available. However, they are associated with significant adverse effects and a growing number of drug-resistant microorganisms and require parenteral administration. Besides that, many trypanosomatid diseases are zoonotic, making eradication extremely difficult. In this way, despite scientific progress over the years, some drug discovery goals remain unmet, such as the development of new therapeutic classes, reduced toxicity, improved administration regimens, or the development of combination therapies. Therefore, this chapter intends to present the six categories of drugs, i.e., the currently used therapeutic agents, nitroaromatic compounds, azole antifungal, benzoxaboroles, nitrogen heterocycles, and miscellaneous agents in clinical trials for NTDs, focusing on infections caused by trypanosomatids. In addition, the review approach presents the development process of the new drugs or treatment regimens in Phase I, II, III, and IV studies of the clinical trials based on the Drugs for Neglected Diseases initiative (DNDi) portfolio published in December 2020.

Nitroheterocyclics have been used for treating infections since the beginning of the 20th century, however, because of their potential toxicities, they have not been exploited thoroughly, except for a few well known drugs like metronidazole. With the growing threat of multidrug resistant tuberculosis in the last two decades, and interesting preliminary results obtained for nitro heterocyclics, their potential as antituberculosis agents has been realised relatively recently.

Thus, after a gap of several decades, nitroheterocyclics are in the forefront amongst the newer scaffolds that have shown utility in treating TB, with five molecules containing the nitro functionality in various phases of clinical trials as well as therapeutic use. Interestingly, these compounds act by multiple different mechanisms of action, and this aspect can be explored further for designing newer molecules.

This review presents a detailed discussion of chemical properties of nitro compounds, the importance of which is highlighted in their mechanisms of action as well as toxicity. This is followed by their classification according to the heterocyclic structures, leading to an understanding of mechanisms of action, structure activity relationship and toxicity. Thus, this review about the current status of nitro containing compounds as anti-TB agents could aid in the design of newer molecules containing nitroheterocyclics in the scaffolds, and maintain optimum balance between anti-TB potency and potential toxicity.

COVID-19, an infectious disease caused by SARS-CoV-2, has impacted human lives since its first outbreak in China and became a pandemic within a short span. As on 20th April 2022, the WHO reported 504,079,039 confirmed COVID-19 cases and 6,204,155 deaths globally.

To combat COVID-19, a number of vaccination drives have been initiated, including vaccines such as Comirnaty and Spikevax approved by the FDA, while several others remain in the process of development or under emergency use authorization. On the other hand, Remdesivir, Baricitinib, in combination with Remdesivir, Paxlovid (Nirmatrelvir tablets and Ritonavir tablets, co-packaged for oral use), molnupiravir and monoclonal antibodies like Regen-COV (Casirivimab and Imdevimab combination), Sotrovimab, Bamlanivinab-Etesevimab combination are also approved for emergency use by US-FDA, but they have their own limitations.

In this view, four major target proteins of SARS-CoV-2 viz spike, envelop, membrane, nucleocapsid, have been identified for the design and discovery of new drug candidates. However, the main protease (Mpro) played a vital part in virus replication and transcription via extensive poly protein proteolysis. Thus, this has been considered as a promising therapeutic target.

In the search of new agents for COVID-19, natural products have also been explored, as they are one of valuable sources of therapeutic agents. Different plant-derived compounds, secondary metabolites, spices, honeybee constituents, lichen derivatives, and compounds of microbial and marine origins exhibiting vivid biological activities, have been reported to inhibit Mpro in in-silico studies. This chapter discusses and highlights the potential prospects of natural products, which can inhibit Mpro and might serve as drugs of the future or as leads for combating SARS-CoV-2.