title: Virtual screening, molecular dynamics, and binding free energy calculations on human carbonic anhydrase IX catalytic domain for deciphering potential leads.
abstract: Carbonic anhydrase IX is a tumor-associated membrane-bound metallo-enzyme which catalyzes the reversible hydration of carbon dioxide (CO2) to bicarbonate (HCO3-) and proton (H+) ions. It is a hypoxia-inducible enzyme and plays a critical role in tumor pH homeostasis favoring tumor cell invasiveness and drug resistance. Over expression of CAIX is documented in cancers of breast, lung, kidney, colon/rectum, etc. Chemical inhibition of CAIX activity has proven to be an effective therapeutic modality towards targeting cancer. Hence, in this study, we intend to identify potential molecules from NCI (National Cancer Institute) and Maybridge databases implementing high-throughput virtual screening. CAIX co-crystallized with acetazolamide (a known inhibitor of CAIX) (PDB ID: 3IAI) was used for reference-guided docking protocol. The potential inhibitors among the coupled data sets were finalized based on Glide docking score, Prime/MMGBSA scoring, significant intermolecular interactions, ADMET (absorption, distribution, metabolism and excretion, toxicity) prediction and stability of complex formation, molecular dynamics simulation, and comparative analysis. By this study, we propose NSC_93618, NSC_170253, NSC_93618, JFD03677, SEW06488, and BTB09372 to be highly significant, as all these compounds were found to qualify as potential leads surpassing all the stringent filtering process. However, NSC_93618 was found to be the most potential, as it featured with higher complex stability with strong bonded interactions, binding affinity synonymous to acetazolamide. Hence, these proposed compounds shall prove to be effective in targeting CAIX towards modulating carcinogenesis.
authors.affiliation: a Centre for Bioinformatics, Kamalnayan Bajaj Institute for Research in Vision and Ophthalmology, Vision Research Foundation , Sankara Nethralaya , Chennai 600006 , Tamil Nadu , India.|c School of Chemical and Biotechnology , SASTRA University , Thanjavur , Tamil Nadu , India.
authors.forename: Arun
authors.initials: A
authors.lastname: John
authors.affiliation: a Centre for Bioinformatics, Kamalnayan Bajaj Institute for Research in Vision and Ophthalmology, Vision Research Foundation , Sankara Nethralaya , Chennai 600006 , Tamil Nadu , India.|c School of Chemical and Biotechnology , SASTRA University , Thanjavur , Tamil Nadu , India.
authors.forename: Muthukumaran
authors.initials: M
authors.lastname: Sivashanmugam
authors.affiliation: a Centre for Bioinformatics, Kamalnayan Bajaj Institute for Research in Vision and Ophthalmology, Vision Research Foundation , Sankara Nethralaya , Chennai 600006 , Tamil Nadu , India.
authors.forename: Vetrivel
authors.initials: V
authors.lastname: Umashankar
authors.affiliation: b R.S. Mehta Jain Department of Biochemistry and Cell Biology, Kamalnayan Bajaj Institute for Research in Vision and Ophthalmology, Vision Research Foundation , Sankara Nethralaya , Chennai 600006 , Tamil Nadu , India.
authors.forename: Sulochana Konerirajapuram
authors.initials: SK
authors.lastname: Natarajan
mesh_terms: D000086:Acetazolamide / Q000737:chemistry*; D020816:Amino Acid Motifs; D000951:Antigens, Neoplasm / Q000737:chemistry*; D000071231:Carbonic Anhydrase IX / Q000037:antagonists & inhibitors / Q000737:chemistry*; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry*; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D057166:High-Throughput Screening Assays; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D054730:Protein Interaction Domains and Motifs; D013379:Substrate Specificity; D013816:Thermodynamics; D014584:User-Computer Interface
chemical_list: D000951:Antigens, Neoplasm; D002257:Carbonic Anhydrase Inhibitors; D009363:Neoplasm Proteins; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D000086:Acetazolamide
keywords: Prime/MM-GBSA; carbonic anhydrase IX; molecular docking; molecular dynamics; virtual screening