Department of Pharmacy
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Item Identification of synthetically tractable MERS-CoV main protease inhibitors using structure-based virtual screening and molecular dynamics potential of mean force (PMF) calculations(Taylor & Francis, 2023-11) Sundriyal, SandeepThe Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is a potentially lethal infection that presents a substantial threat to health, especially in Middle East nations. Given that no FDA-approved specific therapy for MERS infection exists, designing and discovering a potent antiviral therapy for MERS-CoV is crucial. One pivotal strategy for inhibiting MERS replication is to focus on the viral main protease (Mpro). In this study, we identify potential novel Mpro inhibitors employing structure-based virtual screening of our recently reported Ugi reaction-derived library (URDL) consisting of cherry-picked molecules from the literature. The key features of the URDL library include synthetic tractability (1–2 pot synthesis) of the molecules scaffold and unexplored chemical space. The hits were ranked based on the docking score, MM-GBSA free energy of binding, and the interaction pattern with the active site residues. A molecular dynamics (MD) simulation study was performed for the first two top-ranked compounds to analyze the stability and free binding energy based on the molecular mechanics Poisson-Boltzmann surface area. The potential mean force calculated from the steered molecular dynamics (SMD) simulations of the hits indicates improved H-bond potential, enhanced conformational stability, and binding affinity toward the target, compared to the cocrystallized ligand. The discovered hits represent novel synthetically tractable scaffolds as potential MERS-CoV Mpro inhibitors.Item Identification of synthetically tractable MERS-CoV main protease inhibitors using structure-based virtual screening and molecular dynamics potential of mean force (PMF) calculations(Taylor & Francis, 2023-11) Sundriyal, SandeepThe Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is a potentially lethal infection that presents a substantial threat to health, especially in Middle East nations. Given that no FDA-approved specific therapy for MERS infection exists, designing and discovering a potent antiviral therapy for MERS-CoV is crucial. One pivotal strategy for inhibiting MERS replication is to focus on the viral main protease (Mpro). In this study, we identify potential novel Mpro inhibitors employing structure-based virtual screening of our recently reported Ugi reaction-derived library (URDL) consisting of cherry-picked molecules from the literature. The key features of the URDL library include synthetic tractability (1–2 pot synthesis) of the molecules scaffold and unexplored chemical space. The hits were ranked based on the docking score, MM-GBSA free energy of binding, and the interaction pattern with the active site residues. A molecular dynamics (MD) simulation study was performed for the first two top-ranked compounds to analyze the stability and free binding energy based on the molecular mechanics Poisson-Boltzmann surface area. The potential mean force calculated from the steered molecular dynamics (SMD) simulations of the hits indicates improved H-bond potential, enhanced conformational stability, and binding affinity toward the target, compared to the cocrystallized ligand. The discovered hits represent novel synthetically tractable scaffolds as potential MERS-CoV Mpro inhibitors.Item Discovery of small molecule inhibitors of Mycobacterium tuberculosis ClpC1: SAR studies and antimycobacterial evaluation(Elsevier, 2023-01) Sundriyal, SandeepThe emergence of drug-resistant strains of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB) in humans, is a primary reason for treatment failure. Currently, only limited options are available for the management of multi-drug resistant TB, warranting the design of novel anti-TB drugs by exploiting newer targets. One of the caseinolytic protease (Clp) machinery components, an unfoldase known as ClpC1, has emerged as a distinct anti-TB drug target owing to its essential role in the pathogen's survival. The naturally occurring cyclic peptides targeting the Mtb ClpC1, exhibit potent antimycobacterial activity. However, the large, complex, and poor synthetic tractability of these peptides limit their clinical application. Identification of small molecule inhibitors of Mtb ClpC1 will be useful for future drug development. Here, we report the discovery of a bisquinoline chemotype from the screening of a small molecule chemical library against Mtb ClpC1. The hit molecule binds with ClpC1 and exhibits dose-dependent inhibition of its enzymatic activity by direct binding. The in vitro growth of Mtb is inhibited by the hit molecule at a minimum inhibitory concentration of 12.5 µM. Investigation of the structure–activity relationship by chemical synthesis underlines the requirement of the two quinoline rings, 9/10 carbon linker, and the importance of basic ring nitrogen for its inhibitory activity. To our knowledge, this is the first report on the systematic analysis of small molecule inhibitors of Mtb ClpC1.Item Identification of a new and diverse set of Mycobacterium tuberculosis uracil-DNA glycosylase (MtUng) inhibitors using structure-based virtual screening: Experimental validation and molecular dynamics studies(Elsevier, 2022-11) Sundriyal, SandeepMycobacterium tuberculosis uracil-DNA glycosylase (MtUng), a key DNA repair enzyme, represents an attractive target for the design of new antimycobacterial agents. However, only a limited number of weak MtUng inhibitors are reported, primarily based on the uracil ring, and hence, lack diversity. We report the first structure-based virtual screening (SBVS) using three separate libraries consisting of uracil and non-uracil small molecules, together with the FDA-approved drugs. Twenty diverse virtual hits with the highest predicted binding were procured and screened using a fluorescence-based assay to evaluate their potential to inhibit MtUng. Several of these molecules were found to inhibit MtUng activity at low mM and µM levels, comparable to or better than several other reported Ung inhibitors. Thus, these molecules represent a diverse set of scaffolds for developing next-generation MtUng inhibitors. The most active uracil-based compound 5 (IC50 = 0.14 mM) was found to be ∼ 15-fold more potent than the positive control, uracil. The binding stability and conformation of compound 5 in complex with the enzyme were further confirmed using molecular dynamics simulation