The COVID-19 pandemic is an ongoing global health emergency caused by a newly discovered coronavirus SARS-CoV-2. The entire scientific community across the globe is working diligently to tackle this unprecedented challenge. In silico studies have played a crucial role in the current situation by expediting the process of identification of novel potential chemotypes targeting the viral receptors. In this study, we have made efforts to identify molecules that can potentially inhibit the SARS-CoV-2 main protease (M pro) using the high-resolution crystal structure of SARS-CoV-2 M pro. The SARS-CoV-2 M pro has a large flexible binding pocket that can accommodate various chemically diverse ligands but a complete occupation of the binding cavity is necessary for efficient inhibition and stability. We augmented glide three-tier molecular docking protocol with water thermodynamics to screen molecules obtained from three different compound libraries. The diverse hits obtained through docking studies were scored against generated WaterMap to enrich the quality of results. Five molecules were selected from each compound library on the basis of scores and protein-ligand complementarity. Further MD simulations on the proposed molecules affirm the stability of these molecules in the complex. MM-GBSA results and intermolecular hydrogen bond analysis also confirm the thermodynamic stability of proposed molecules. This study also presumably steers the structure determination of many ligandmain protease complexes using x-ray diffraction methods.
The Coronavirus pandemic has put the entire humanity in total shock and has forced the world to go under total lockdown. It is time for the entire scientific community across the globe to find a solution for this deadly and unseen enemy. In silico studies play a vital role in situations like this, as experimental studies are not feasible by all researchers particularly with relevance to BSL4 procedures. In this study, using the high resolution crystal structure of SARS-CoV-2 main protease (PDB: 5R82), we have identified molecules which can potentially inhibit the main protease (Mpro). We used a three-tier docking protocol making use of three different databases. We analysed the residues which are lying near the ligand binding pocket of the main protease structure and it shows a wide cavity, which can accommodate chemically diverse ligands, occupying different sub-pockets. Using the small fragment bound in the 5R82, we have identified several larger molecules whose functional groups make interactions with the active site residues covering. This study also presumably steers the structure determination of many ligand-main protease complexes using x- ray diffraction methods. These molecules can be used as ‘in silico leads’ and further be explored in the development of SARS-CoV-2 drugs.
“India fights Corona”, proclaims the media. ‘Stay home’, ‘social distancing’, ‘lock down’ are the phrases ringing in every home. The Corona pandemic has drawn the attention of many scientists to fight against the virus. We report herein, a set of newly identified molecules which can presumably act as potential inhibitors of Covid-19 main protease. A fast mode approach using a combinatorial structure based strategy which includes high throughput virtual screening, molecular docking, water map calculations and data base search was applied to identify these molecules. The PDB structures, 5R82, 6Y2G were used as the basis for this study. Data bases viz., Enamine, Drug Bank, Natural product, Specs and few antiviral drugs were used for screening. Water map analysis yielded insights into the design of more potential molecules. Considering the need of the hour, this study may help in the discovery and development of anti-viral drugs against Covid-19.
Background: Although water is regarded as a simple molecule, its ability to create hydrogen bonds makes it a highly complex molecule that is crucial to molecular biology. Water molecules are extremely small and are made up of two different types of atoms, each of which plays a particular role in biological processes. Despite substantial research, understanding the hydration chemistry of protein-ligand complexes remains difficult. Researchers are working on harnessing water molecules to solve unsolved challenges as a result of the development of computer technologies. Objective: The goal of this review is to highlight the relevance of water molecules in protein environments, as well as to demonstrate how the lack of well-resolved crystal structures of proteins functions as a bottleneck in developing molecules that target critical therapeutic targets. In addition, the purpose of this article is to give a common platform for researchers to consider numerous aspects connected to water molecules. Conclusion: Considering structure-based drug design, this review will make readers aware of the different aspects related to water molecules. It will provide an amalgamation of information related to the protein environment, linking the thermodynamic fingerprints of water with key therapeutic targets. The review has mentioned about a large number of computational tools available to study the water network chemistry with the surrounding protein enviornment. It also emphasises the need for computational methods in addressing gaps left by a poorly resolved crystallized protein structure.
The COVID-19 outbreak has thrown the world into an unprecedented crisis. It has posed a challenge to scientists around the globe who are working tirelessly to combat this pandemic. We herein report a set of molecules that may serve as possible inhibitors of the SARS-CoV-2 main protease. To identify these molecules, we followed a combinatorial structure-based strategy, which includes high-throughput virtual screening, molecular docking and WaterMap calculations. The study was carried out using Protein Data Bank structures 5R82 and 6Y2G. DrugBank, Enamine, Natural product and Specs databases, along with a few known antiviral drugs, were used for the screening. WaterMap analysis aided in the recognition of high-potential molecules that can efficiently displace binding-site waters. This study may help the discovery and development of antiviral drugs against SARS-CoV-2.
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