"Identification of alkaloid compounds as potent inhibitors of Mycobacterium tuberculosis NadD using computational strategies".

Mycobacterium tuberculosis is leading cause of death worldwide. NAD participates in a host of redox reactions in energy landscape of organisms. Several studies implicate surrogate energy pathways involving NAD pools as important in survival of active as well as dormant mycobacteria. One of the NAD metabolic pathway enzyme, nicotinate mononucleotide adenylyltransferase (NadD) is indispensable in mycobacterial NAD metabolism and is perceived as an attractive drug target in pathogen. In this study, we have employed in silico screening, simulation and MM-PBSA strategies to identify potentially important alkaloid compounds against mycobacterial NadD for structure-based inhibitor development. We have performed an exhaustive structure-based virtual screening of an alkaloid library, ADMET, DFT profiling followed by Molecular Dynamics (MD) simulation, and Molecular Mechanics-Poisson Boltzmann Surface Area (MM-PBSA) calculation to identify 10 compounds which exhibit favourable drug like properties and interactions. Interaction energies of these 10 alkaloid molecules range between -190 kJ/mol and -250 kJ/mol. These compounds could be promising starting point in the development of selective inhibitors against Mycobacterium tuberculosis.

Neohesperidin and spike RBD interaction in omicron and its sub-variants: In silico, structural and simulation studies.

COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged first around December 2019 in the city of Wuhan, China. Since then, several variants of the virus have emerged with different biological properties. This pandemic has so far led to widespread infection cycles with millions of fatalities and infections globally. In the recent cycle, a new variant omicron and its three sub-variants BA.1, BA.2 and BA.3 have emerged which seems to evade host immune defences and have brisk infection rate. Particularly, BA.2 variant has shown high transmission rate over BA.1 strain in different countries including India. In the present study, we have evaluated a set of eighty drugs/compounds using in silico docking calculations in omicron and its variants. These molecules were reported previously against SARS-CoV-2. Our docking and simulation analyses suggest differences in affinity of these compounds in omicron and BA.2 compared to SARS-CoV-2. These studies show that neohesperidin, a natural flavonoid found in Citrus aurantium makes a stable interaction with spike receptor domain of omicron and BA.2 compared to other variants. Free energy binding analyses further validates that neohesperidin forms a stable complex with spike RBD in omicron and BA.2 with a binding energy of -237.9 ± 18.7 kJ/mol and -164.1 ± 17.5 kJ/mol respectively. Key residual differences in the RBD interface of these variants form the basis for differential interaction affinities with neohesperidin as drug binding site overlaps with RBD-human ACE2 interface. These data might be useful for the design and development of novel scaffolds and pharmacophores to develop specific therapeutic strategies against these novel variants.