title: QSAR and docking studies on capsazepine derivatives for immunomodulatory and anti-inflammatory activity.
abstract: Capsazepine, an antagonist of capsaicin, is discovered by the structure and activity relationship. In previous studies it has been found that capsazepine has potency for immunomodulation and anti-inflammatory activity and emerging as a favourable target in quest for efficacious and safe anti-inflammatory drug. Thus, a 2D quantitative structural activity relationship (QSAR) model against target tumor necrosis factor-α (TNF-α) was developed using multiple linear regression method (MLR) with good internal prediction (r2 = 0.8779) and external prediction (r2pred = 0.5865) using Discovery Studio v3.5 (Accelrys, USA). The predicted activity was further validated by in vitro experiment. Capsazepine was tested in lipopolysaccharide (LPS) induced inflammation in peritoneal mouse macrophages. Anti-inflammatory profile of capsazepine was assessed by its potency to inhibit the production of inflammatory mediator TNF-α. The in vitro experiment indicated that capsazepine is an efficient anti-inflammatory agent. Since, the developed QSAR model showed significant correlations between chemical structure and anti-inflammatory activity, it was successfully applied in the screening of forty-four virtual derivatives of capsazepine, which finally afforded six potent derivatives, CPZ-29, CPZ-30, CPZ-33, CPZ-34, CPZ-35 and CPZ-36. To gain more insights into the molecular mechanism of action of capsazepine and its derivatives, molecular docking and in silico absorption, distribution, metabolism, excretion and toxicity (ADMET) studies were performed. The results of QSAR, molecular docking, in silico ADMET screening and in vitro experimental studies provide guideline and mechanistic scope for the identification of more potent anti-inflammatory & immunomodulatory drug.
authors.affiliation: Metabolic and Structural Biology Department, CSIR-Central Institute of Medicinal and Aromatic Plants, P.O.- CIMAP, Kukrail Picnic Spot Road, Lucknow (Uttar Pradesh), India.
authors.forename: Aparna
authors.initials: A
authors.lastname: Shukla
authors.affiliation: Metabolic and Structural Biology Department, CSIR-Central Institute of Medicinal and Aromatic Plants, P.O.- CIMAP, Kukrail Picnic Spot Road, Lucknow (Uttar Pradesh), India.
authors.forename: Pooja
authors.initials: P
authors.lastname: Sharma
authors.affiliation: Metabolic and Structural Biology Department, CSIR-Central Institute of Medicinal and Aromatic Plants, P.O.- CIMAP, Kukrail Picnic Spot Road, Lucknow (Uttar Pradesh), India.
authors.forename: Om
authors.initials: O
authors.lastname: Prakash
authors.affiliation: Molecular Bio-Prospection Department, CSIR-Central Institute of Medicinal and Aromatic Plants, P.O.- CIMAP, Kukrail Picnic Spot Road, Lucknow (Uttar Pradesh), India.
authors.forename: Monika
authors.initials: M
authors.lastname: Singh
authors.affiliation: Analytical Chemistry Division, CSIR-Central Institute of Medicinal and Aromatic Plants, P.O.- CIMAP, Kukrail Picnic Spot Road, Lucknow (Uttar Pradesh), India.
authors.forename: Komal
authors.initials: K
authors.lastname: Kalani
authors.affiliation: Metabolic and Structural Biology Department, CSIR-Central Institute of Medicinal and Aromatic Plants, P.O.- CIMAP, Kukrail Picnic Spot Road, Lucknow (Uttar Pradesh), India.
authors.forename: Feroz
authors.initials: F
authors.lastname: Khan
authors.affiliation: Molecular Bio-Prospection Department, CSIR-Central Institute of Medicinal and Aromatic Plants, P.O.- CIMAP, Kukrail Picnic Spot Road, Lucknow (Uttar Pradesh), India.
authors.forename: Dnyaneshwar Umrao
authors.initials: DU
authors.lastname: Bawankule
authors.affiliation: Molecular Bio-Prospection Department, CSIR-Central Institute of Medicinal and Aromatic Plants, P.O.- CIMAP, Kukrail Picnic Spot Road, Lucknow (Uttar Pradesh), India.
authors.forename: Suaib
authors.initials: S
authors.lastname: Luqman
authors.affiliation: Analytical Chemistry Division, CSIR-Central Institute of Medicinal and Aromatic Plants, P.O.- CIMAP, Kukrail Picnic Spot Road, Lucknow (Uttar Pradesh), India.
authors.forename: Santosh Kumar
authors.initials: SK
authors.lastname: Srivastava
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D002211:Capsaicin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D005260:Female; D007155:Immunologic Factors / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D018570:Risk Assessment; D014409:Tumor Necrosis Factor-alpha / Q000737:chemistry / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D007155:Immunologic Factors; D014409:Tumor Necrosis Factor-alpha; C071423:capsazepine; D002211:Capsaicin