The pandemic caused by novel coronavirus disease 2019 infecting millions of populations worldwide and counting, has demanded quick and potential therapeutic strategies. Current approved drugs or molecules under clinical trials can be a good pool for repurposing through in-silico techniques to quickly identify promising drug candidates. The structural information of recently released crystal structures of main protease (M pro ) in APO and complex with inhibitors, N3, and 13b molecules was utilized to explore the binding site architecture through Molecular dynamics (MD) simulations. The stable state of M pro was used to conduct extensive virtual screening of the aforementioned drug pool. Considering the recent success of HIV protease molecules, we also used anti-protease molecules for drug repurposing purposes. The identified top hits were further evaluated through MD simulations followed by the binding free energy calculations using MM-GBSA. Interestingly, in our screening, several promising drugs stand out as potential inhibitors of M pro . However, based on control (N3 and 13b), we have identified six potential molecules, Leupeptin Hemisulphate, Pepstatin A, Nelfinavir, Birinapant, Lypression and Octreotide which have shown the reasonably significant MM-GBSA score. Further insight shows that the molecules form stable interactions with hot-spot residues, that are mainly conserved and can be targeted for structure-and pharmacophore-based designing. The pharmacokinetic annotations and therapeutic importance have suggested that these molecules possess drug-like properties and pave their way for in-vitro studies. ARTICLE HISTORY

<p>In this work, computer-aided drug design method has been implemented to quickly identify promising drug repurposing candidates against COVID-19 main protease (M^pro). The world is facing an epidemic and in absence of vaccine or any effective treatment, it has created a sense of urgency for novel drug discovery approaches. We have made an immediate effort by performing virtual screening of clinically approved drugs or molecules under clinical trials against COVID-19 M^pro to identify potential drug molecules. With given knowledge of this system, N3 and 13B compounds have shown inhibitory effect against COVID-19 M^pro. Both the compounds were considered as control to filter out the screened molecules. Overall, we have identified six potential compounds, Leupeptin Hemisulphate, Pepstatin A, Nelfinavir , Birinapant, Lypression and Octeotide which have shown the docking energy > -8.0 kcal/mol and MMGBSA > -68.0 kcal/mol. The binding pattern of these compounds suggests that they interacted with key <i>hot-spot</i> residues. Also, their pharmacokinetic annotations and therapeutic importance have indicated that they possess drug-like properties and could pave their way for<i> in-vitro</i> studies. The findings of this work will be significant for structure and pharmacophore-based designing. </p>

The dynamics and plasticity of the PD-1/PD-L1 axis are the bottlenecks for the discovery of small-molecule antagonists to perturb this interaction interface significantly. Understanding the process of this protein−protein interaction (PPI) is of fundamental biological interest in structure-based drug designing. Food and Drug Administration (FDA)-approved anti-PD-1 monoclonal antibodies (mAbs) are the first-in-class with distinct binding modes to access this axis clinically; however, their mechanistic aspects remain elusive. Here, we have unveiled the interactive interfaces with PD-L1 and mAbs to investigate the native plasticity of PD-1 at global (structural and dynamical) and local (residue side-chain orientations) levels. We found that the structural stability and coordinated C α movements are increased in the presence of PD-1's binding partners. The rigorous analysis of these PPIs using computational biophysical approaches revealed PD-1ʼs intrinsic plasticity, its concerted loops' movement (BC, FG, and CC′), distal side-chain motions, and the thermodynamic landscape, which are perturbed remarkably from its unbound to bound states. Based on intra-/inter-residues' contact networks and energetics, the hot-spots have been identified that were found to be essential to arrest the dynamical motions of PD-1 significantly for the rational design of therapeutic agents by mimicking the mAbs mechanism.

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RNA-dependent RNA polymerase (RdRp) is a relevant antiviral drug target. We investigated a potent benzimidazole inhibitor (227G; IC 50 = 0.002 μM) against bovine viral diarrhea virus (BVDV) RdRp; however, its inhibition action was completely impaired in the presence of a resistant mutation, I261M. The binding of 227G in mutant RdRp affected the binding site loop conformations (especially Linker) that increased the volume of the binding site. It was also observed that the innate Linker's flexibility was retained, which was otherwise completely frozen in the wild-type complex. The functional role of Linker was hypothesized that it is a multidocking site for RNA template, inhibitors, and the other proteins involved in replication complex formation. The binding phenomenon requires significant molecular flexibility and the large-amplitude conformational dynamics of Linker, which is currently unknown. We observed a bidirectional "hinge"-like motion of Linker from crystal position, indicating its pronounced flexible behavior. This study underscores the importance of Linker's flexibility in the functionality of BVDV RdRp and proposes the template entrance site for selective anti-BVDV drug discovery.

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<p>In this work, Computer-aided drug design method has been implemented to quickly identify promising drug repurposing candidates against COVID-19. The world is facing an epidemic and in absence of vaccine or any effective treatment, it has created a sense of urgency for novel drug discovery approaches. We have made an immediate effort by performing virtual screening of clinically approved drugs or molecules under clinical trials against COVID-19 to identify potential drug molecules.</p> <p>With given knowledge of this system, N3 and 13B compounds have shown inhibitory effect against COVD-19. Both the compounds were considered as control to filter out the screened molecules. Overall, we have identified six potential compounds, Leupeptin Hemisulphate, Pepstatin A, Nelfinavir , Birinapant, Lypression and Octeotide which have shown the docking energy > -8 kcal/mol and MMGBSA > -90 kcal/mol. The binding pattern of these compounds suggests that they interact with key <i>hot-spot</i> residues. Also, the pharmacokinetic annotations and their biological activity have indicated that they possess drug-like properties and pave their way for in vitro studies</p> <p>The findings of this work will be significant for structure and pharmacophore-based designing</p>

The ability to predict the intricate mechanistic behavior of ligands and associated structural determinants during protein-ligand (un)binding is of great practical importance in drug discovery. Ubiquitin specific protease-7 (USP7) is a newly emerging attractive cancer therapeutic target with bound allosteric inhibitors. However, none of the inhibitors have reached clinical trials, allowing opportunities to examine every aspect of allosteric modulation. The crystallographic insights reveal that these inhibitors have common properties such as chemical scaffolds, binding site and interaction fingerprinting. However, they