NOD: a web server to predict New use of Old Drugs to facilitate drug repurposing.

Computational methods accelerate the drug repurposing pipelines that are a quicker and cost-effective alternative to discovering new molecules. However, there is a paucity of web servers to conduct fast, focussed, and customized investigations for identifying new uses of old drugs. We present the NOD web server, which has the mentioned characteristics. NOD uses a sensitive sequence-guided approach to identify close and distant homologs of a protein of interest. NOD then exploits this evolutionary information to suggest potential compounds from the DrugBank database that can be repurposed against the input protein. NOD also allows expansion of the chemical space of the potential candidates through similarity searches. We have validated the performance of NOD against available experimental and/or clinical reports. In 65.6% of the investigated cases in a control study, NOD is able to identify drugs more effectively than the searches made in DrugBank. NOD is freely-available at http://pauling.mbu.iisc.ac.in/NOD/NOD/ .

'All That Glitters Is Not Gold': High-Resolution Crystal Structures of Ligand-Protein Complexes Need Not Always Represent Confident Binding Poses.

Our understanding of the structure-function relationships of biomolecules and thereby applying it to drug discovery programs are substantially dependent on the availability of the structural information of ligand-protein complexes. However, the correct interpretation of the electron density of a small molecule bound to a crystal structure of a macromolecule is not trivial. Our analysis involving quality assessment of ~0.28 million small molecule-protein binding site pairs derived from crystal structures corresponding to ~66,000 PDB entries indicates that the majority (65%) of the pairs might need little (54%) or no (11%) attention. Out of the remaining 35% of pairs that need attention, 11% of the pairs (including structures with high/moderate resolution) pose serious concerns. Unfortunately, most users of crystal structures lack the training to evaluate the quality of a crystal structure against its experimental data and, in general, rely on the resolution as a 'gold standard' quality metric. Our work aims to sensitize the non-crystallographers that resolution, which is a global quality metric, need not be an accurate indicator of local structural quality. In this article, we demonstrate the use of several freely available tools that quantify local structural quality and are easy to use from a non-crystallographer's perspective. We further propose a few solutions for consideration by the scientific community to promote quality research in structural biology and applied areas.

Repurposing drugs against the main protease of SARS-CoV-2: mechanism-based insights supported by available laboratory and clinical data.

The ongoing global pandemic of COVID-19 has brought life to almost a standstill with the implementation of lockdowns and social distancing as some of the preventive measures in the absence of any approved specific therapeutic interventions. To combat this crisis, research communities worldwide are falling back on the existing repertoire of approved/investigational drugs to probe into their anti-coronavirus properties. In this report, we describe our unique efforts in identifying potential drugs that could be repurposed against the main protease of SARS-CoV-2 (SARS-CoV-2 Mpro). To achieve this goal, we have primarily exploited the principles of 'neighbourhood behaviour' in the protein 3D (workflow-I) and chemical 2D structural space (workflow-II) coupled with docking simulations and insights into the possible modes of action of the selected candidates from the available literature. This integrative approach culminated in prioritizing 29 potential repurpose-able agents (20 approved drugs and 9 investigational molecules) against SARS-CoV-2 Mpro. Apart from the approved/investigational anti-viral drugs, other notable hits include anti-bacterial, anti-inflammatory, anti-cancer and anti-coagulant drugs. Our analysis suggests that some of these drugs have the potential to simultaneously modulate the functions of viral proteins and the host response system. Interestingly, many of these identified candidates (12 molecules from workflow-I and several molecules, belonging to the chemical classes of alkaloids, tetracyclines, peptidomimetics, from workflow-II) are suggested to possess anti-viral properties, which is supported by laboratory and clinical data. Furthermore, this work opens a new avenue of research to probe into the molecular mechanism of action of many drugs, which are known to demonstrate anti-viral activity but are so far not known to target viral proteases.