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CD147/Basigin/EMMPRIN (Extracellular Matrix Metalloproteinase inducer) is a single pass type1 transmembrane protein playing a central role in developmental process, wound healing, nutrient transport, inflammation, arthritis and also in microbial pathologies. It is also found to be a potent stimulator of MMP (matrix metalloproteinases) and has been considered as a prognostic marker in cancer. Dysregulation of CD147 is reported in several types of cancer. It activates cell proliferation, invasion, metastasis and inhibits tumor cell apoptosis under hypoxic condition. Thus, CD147 serves as a hub protein in cancer, as it is involved in several homophilic and heterophilic cellular interactions spanning the major hallmarks of cancer. Targeting these interactions is considered to be an efficient therapeutic modality in cancerous conditions. Hence, by this review we intend to collate the structure-function relationships of CD147, with an exclusive thrust on potential druggable hotspots based on its intra and inter molecular interactions.

Aims Toxoplasma gondii (T. gondii) is an intracellular Apicomplexan parasite and a causative agent of toxoplasmosis in human. Its parasitic invasion leads to encephalitis, uveitis, chorioretinitis and congenital infection. Host invasion by T. gondii is mediated by Moving junction (MJ) complex formed by secretory proteins such as micronemes and Rhoptry Neck proteins (RONs). Among these secretory proteins, RON4 shows major interactions with RON2 and RON5 of MJ complex and is also found to facilitate invasion by interacting with β-tubulin of the host. Therefore, drug targeting of RON4 is considered to be an effective modality to inhibit host invasion. Main methods Hence, in this study, we have implemented High throughput virtual screening (HTVS) against predicted novel druggable cavity on RON4, in order to prioritize potential inhibitors. This study also specifically focuses on identifying potential drugs that are ocular accommodative towards targeting ocular toxoplasmosis. Thus, the small molecules resulting from HTVS were subjected to stringent multi-level precision screening which involves PASS prediction, Density functional theory analysis, Binding Free Energy Calculations and stability of complex formation during molecular dynamics simulation to prioritize the potential hits. Key findings Among the compounds from NCI chemical library, five (338683, 333739, 686585, 159706, 405935) were found to surpass all the stringent filtration criteria. Significance Based on comparatively analysis, it was inferred that 333739 (benzyl 2-((2-(((benzyloxy) carbonyl) amino)-3-hydroxybutanoyl) amino) propanoate) to be highly potential in comparison to other compounds and shall prove to be an efficient inhibitor of RON4 in ocular toxoplasmosis.

High throughput virtual screening plays a crucial role in hit identification during the drug discovery process. With the rapid increase in the chemical libraries, virtual screening process becomes computationally challenging, thereby posing a demand for efficiently parallelized software pipelines. Here we present a GNU Parallel based pipeline-POAP that is programmed to run Open Babel and AutoDock suite under highly optimized parallelization. The ligand preparation module is a unique feature in POAP, as it offers extensive options for geometry optimization, conformer generation, parallelization and also quarantines erroneous datasets for seamless operation. POAP also features multi receptor docking that can be utilized for comparative virtual screening and drug repurposing studies. As demonstrated using different structural datasets, POAP proves to be an efficient pipeline that enables high scalability, seamless operability, dynamic file handling and optimal utilization of CPU’s for computationally demanding tasks. POAP is distributed freely under GNU GPL license and can be downloaded at https://github.com/inpacdb/POAP .

Glaucoma is the second leading cause of blindness in the world and is characterized by the loss of retinal ganglion cells (RGC) over a period of time, leading to complete blindness. Recently, endothelin has been identified as an important factor that influences intraocular pressure IOP, OBF, and direct RGC damage. Targeting the endothelin receptor signaling pathway in glaucoma is considered to be highly beneficial, as it can effectively modulate IOP, OBF, and RGC damage, the key factors which are essential to modulate the disease progression holistically. Currently, synthetic drugs like Bosentan, BQ-123, and prostaglandin analogues are available as endothelin receptor antagonists, which are extensively used in the treatment of cardiovascular and other conditions like systemic hypertension. However, the usage of these drugs in glaucoma is limited due to toxicity and poor bioavailability in the ocular milieu. Thus, there is a need for potential natural compounds as endothelin receptor antagonists that acts as dual inhibitors by targeting both ETA and ETB and are highly efficient with the least toxicity. Hence, this study is intended to prioritize endothelin receptor antagonists by structural bioinformatics approaches involving molecular modeling, molecular dynamics, and molecular docking studies. Subsequently, High throughput virtual screening (HTVS) vs. Natural compound databases targeting the optimal binding sites of both ETA and ETB. Following this, the common hits were subjected to binding free energy calculations (MMGBSA) and ADMETox analysis. Finally, the most potential hits were analyzed for MD based binding stability analysis and binding free energy. Similarly, the known synthetic inhibitors were also docked to the receptors and the results were analyzed. From this study, it was inferred that among the natural compounds dataset (8929 compounds), only 4 common compounds were identified as hits. Among these, only one compound ST075640 surpassed all the prioritization criteria including MMGBSA, ADMETox prediction, dual inhibitory potential (ETA & ETB), and also in structural comparative analysis with bosentan it showed similar efficiency. Thus, the validated hit shall prove to be effective in modulating endothelin mediated IOP, OBF, and RGC damage in glaucomatous condition.

Mycotic keratitis has emerged as a major ophthalmic problem and a leading cause of blindness, since its recognition in 1879. Filamentous fungi are major causative of mycotic keratitis. In India, the main etiological organism responsible for mycotic keratitis is Aspergillus species followed by Fusarium species. In South India, Fusarium based keratitis scales up to 43%. Nearly one-third of mycotic keratitis treatment results in failure, as fungal infections are highly resistant to antibiotic therapies. Therefore, there is need to determine novel and specific targets to constrain Fusarium infections in human eye. In this study, we implemented subtractive proteomics coupled with in silico functional annotation to prioritize potential and specific drug targets which can be used to modulate the virulence of Fusarium solani subsp.pisi (Nectria haematococca MPVI). The results infer that Thiamine thiazole synthase (Thi4), an intracellular membrane bound protein as the potential target, which is a core protein in biological and metabolic process of this pathogen. Moreover, this protein occurs in the thiamine thiazole biosynthesis pathway which is unique to F.solani and devoid in human. Hence, we predicted a plausible structure for this protein and also performed ligand-binding cavity analysis which can be for a strong base for drug designing studies. This study will pave way in better understanding of potential drug targets in F.solani and also leading to therapeutic interventions of fungal keratitis.