Identification of potential human chymase inhibitors using molecular docking and molecular dynamics simulation

Chymase is a hydrolase class of enzymes that involves  hydrolysis of peptide bonds. It is abundant in secretory granules of mast cells. Mast cell chymase is involved in the synthesis of angiotensin-II from its precursor protein. In addition, chymase is involved in converting TGF-β and matrix metalloproteinase to their active form. Chymase involved in heart failure has been proven, and its inhibition may reduce the progression. Hence, to identify the potential inhibitors against the chymase, the present study employed structure-based virtual screening, molecular docking, and molecular dynamics simulation to identify potential chymase inhibitors. Initially, compounds were selected based on their physicochemical and pharmacokinetic properties. Further, the binding affinities using molecular docking and interaction analyses were performed to find potential chymase inhibitors. The study identified chymase inhibitor ZINC000008382327, bearing significant binding affinity, specificity, and efficacy towards the chymase. Next, the stability and binding mode of chymase with ZINC000008382327 were assessed using molecular dynamics simulations. The simulation analysis using root mean square deviations and fluctuations revealed that inhibitor ZINC000008382327 affected the structure and dynamics of the chymase protein. It was also shown that the chymase forms a stable complex with ZINC000008382327 during the simulation. Thus, the present computational study put forward that the identified compound can be further exploited as a potential chemical scaffold to design and develop new human chymase inhibitors

Sialic acids: An Avenue to Target Cancer Progression, Metastasis, and Resistance to Therapy

Abstract Background Sialic acids are alpha-keto acids with nine carbons that are commonly present in the terminal sugars of glycans on glycoproteins and glycolipids on the cell surface. Sialic acids have a role in a variety of physiological and pathological processes by interacting with carbohydrates and proteins, communicating between cells, and acting as cell surface receptors for viruses and bacteria. Several studies have shown the aberrant pattern of sialic acids on cancer cells due to change in their glycosylation status. This pattern may be attributed to various physiological and pathological changes occurring in tumour cells. Hypersialylation in tumours, its involvement in tumour growth, immune evasion and escape from the apoptotic pathway, metastasis formation, and therapeutic resistance have all been fairly well investigated. Methods A PubMed search was conducted and published articles in different studies from 2000 to 2020 were included and reviewed. Here, we discuss current outcomes that emphasize the unfavourable effects of hypersialylation on multiple aspects of tumour genesis, immune evasion, metastasis and resistance to therapy. Conclusion These recent investigations have found that aberrant sialylation is an essential process for tumour cells to evade immune surveillance and maintain their malignancy. Together, these noteworthy views provide a solid platform for designing and developing therapeutic approaches that target hypersialylation of cancer cells. </jats:sec

Identification of potential human chymase inhibitors using molecular docking and molecular dynamics simulation

Chymase is a hydrolase class of enzymes that involves  hydrolysis of peptide bonds. It is abundant in secretory granules of mast cells. Mast cell chymase is involved in the synthesis of angiotensin-II from its precursor protein. In addition, chymase is involved in converting TGF-β and matrix metalloproteinase to their active form. Chymase involved in heart failure has been proven, and its inhibition may reduce the progression. Hence, to identify the potential inhibitors against the chymase, the present study employed structure-based virtual screening, molecular docking, and molecular dynamics simulation to identify potential chymase inhibitors. Initially, compounds were selected based on their physicochemical and pharmacokinetic properties. Further, the binding affinities using molecular docking and interaction analyses were performed to find potential chymase inhibitors. The study identified chymase inhibitor ZINC000008382327, bearing significant binding affinity, specificity, and efficacy towards the chymase. Next, the stability and binding mode of chymase with ZINC000008382327 were assessed using molecular dynamics simulations. The simulation analysis using root mean square deviations and fluctuations revealed that inhibitor ZINC000008382327 affected the structure and dynamics of the chymase protein. It was also shown that the chymase forms a stable complex with ZINC000008382327 during the simulation. Thus, the present computational study put forward that the identified compound can be further exploited as a potential chemical scaffold to design and develop new human chymase inhibitors.</jats:p