VIRTUAL SCREENING STUDIES OF SEAWEED METABOLITES FOR PREDICTING POTENTIAL PPARγ AGONISTS

Objective: Peroxisome Proliferator-Activated Receptor-gamma (PPARγ) is a crucial nuclear hormone receptor, which modulates the transcriptional regulation of lipid and glucose homeostasis. It plays a crucial role in many of the metabolic and inflammatory systems. It is a key target for many of the anti-diabetic medications. Perturbation of PPARγ activity is also observed in many of the cancers involving colon, breast, gastric and lung. Thus, it is considered to be the hub molecule for targeting many of these cellular disorders. Seaweed metabolites have been well documented to be novel structural entities with a broad spectrum of pharmacological values. However, it is yet to be utilized for screening PPARγ agonists.Methods: In this study, virtual screening of PPARγ Ligand Binding Domain (LBD) was performed against the datasets from SeaWeed Metabolite Database (SWMD) using Schrodinger Glide High Throughput Virtual Screening module to identify potential PPARγ agonists. Further, the most potential lead was also subjected to molecular dynamics simulation to infer the stability of complex formation.Results: The results have revealed that bromophenolic compounds from the genus Avrainvillea to interact with documented key residues of LBD involved in agonist interactions. Many other metabolites from the genus Rhodomela, Leathesia, Bifurcaria, Osmundaria, Cymopolia also showed significant interactions with LBD of PPARγ.Conclusion: The insights from this study will pave the way for further exploration of lead compounds from seaweed metabolites targeting PPARγ. Â

Design of human immunodeficiency virus-1 neutralizing peptides targeting CD4-binding site: An integrative computational biologics approach

Peptide therapeutics have recently gained momentum in antiviral therapy due to their increased potency and cost-effectiveness. Interaction of the HIV-1 envelope gp120 with the host CD4 receptor is a critical step for viral entry, and therefore the CD4-binding site (CD4bs) of gp120 is a potential hotspot for blocking HIV-1 infection. The present study aimed to design short peptides from well-characterized CD4bs targeting broadly neutralizing antibodies (bNAbs), which could be utilized as bNAb mimetics for viral neutralization. Co-crystallized structures of HIV-1 gp120 in complex with CD4bs-directed bNAbs were used to derive hexameric peptides using the Rosetta Peptiderive protocol. Based on empirical insights into co-crystallized structures, peptides derived from the heavy chain alone were considered. The peptides were docked with both HIV-1 subtype B and C gp120, and the stability of the peptide–antigen complexes was validated using extensive Molecular Dynamics (MD) simulations. Two peptides identified in the study demonstrated stable intermolecular interactions with SER365, GLY366, and GLY367 of the PHE43 cavity in the CD4 binding pocket, and with ASP368 of HIV-1 gp120, thereby mimicking the natural interaction between ASP368gp120 and ARG59CD4–RECEPTOR. Furthermore, the peptides featured favorable physico-chemical properties for virus neutralization suggesting that these peptides may be highly promising bNAb mimetic candidates that may be taken up for experimental validation.</p

INSIGHTS ON DRUG TARGETING OF TOXOPLASMA GONDII HOST INVASION PROTEINS: A REVIEW

Toxoplasma gondii is an obligate intracellular parasite that infects homoeothermic animals. It is also the major cause of retinochoroiditis in humans.Drugs targeting T. gondii proteins involved in the establishment of host-pathogen interactions is well documented to be an efficient way to combatthe infections. Basically, parasitic invasion of T. gondii occurs by the sequential secretion of apical membrane antigen 1 and rhoptry neck proteins onthe parasite and host cell surfaces, respectively. These proteins operate synergistically and form the moving junction (MJ) complex, thereby, enablingattachment and penetration of the parasite into the host cell. Better understanding of molecular interactions of these proteins is essential to develophighly efficient therapeutic modalities. Hence, by this review it is intended to update the current status of rhoptry and other MJ complex proteins asideal candidates for targeting T. gondii.Keywords: Toxoplasma gondii, Rhoptry proteins, Moving junction complex, Toxoplasmosis

IN SILICO SCREENING OF POTENT PPARGAMMA AGONISTS AMONG NATURAL ANTICANCER COMPOUNDS OF INDIAN ORIGIN

ABSTRACTObjective: Naturally occurring anticancer compounds of Indian origin are well-known for potential therapeutic values. A better understanding ofthe intermolecular interactions of these compounds with peroxisome proliferator-activated receptor gamma (PPARγ) is essential, as its activity isreported in many of the cancers involving colon, breast, gastric, and lung. By this study, it is attempted to perform an in silico screening of naturalanticancer compounds of Indian origin with PPARγ ligand binding domain (LBD). The potential anticancer leads ranked in this study will also exertan additional advantage of PPARγ activity modulation. As PPARγ is also an important nuclear hormone receptor that modulates transcriptionalregulation of lipid and glucose homeostasis and also a key target for many of the anti-diabetic medications, the compounds ranked by this study willalso be utilized for other related therapeutic effects.Methods: This study features in silico screening of compounds from Indian Plant Anticancer compounds database against PPARγ LBD main performedSchrodinger glide virtual screening and docking module to delineate potential PPARγ agonists. Finally, the most potential lead was also subjected tomolecular dynamics simulation to infer the stability of complex formation.Results: The results reveal that majority of the top ranking compounds that interact with LBD was found to be flavonoids, and all these compoundswere found to interact with key residues involved in PPARγ agonist interactions.Conclusion: The leads from this study would be helpful in better understanding of the potential of naturally occurring anticancer compounds ofIndian origin toward targeting PPARγ.Keywords: Peroxisome proliferator-activated receptor-gamma, Agonists, Docking, Natural compounds, Anticancer.Â