5nxg
From Proteopedia
Carbonic Anhydrase II Inhibitor RA1
Structural highlights
Disease[CAH2_HUMAN] Defects in CA2 are the cause of osteopetrosis autosomal recessive type 3 (OPTB3) [MIM:259730]; also known as osteopetrosis with renal tubular acidosis, carbonic anhydrase II deficiency syndrome, Guibaud-Vainsel syndrome or marble brain disease. Osteopetrosis is a rare genetic disease characterized by abnormally dense bone, due to defective resorption of immature bone. The disorder occurs in two forms: a severe autosomal recessive form occurring in utero, infancy, or childhood, and a benign autosomal dominant form occurring in adolescence or adulthood. Autosomal recessive osteopetrosis is usually associated with normal or elevated amount of non-functional osteoclasts. OPTB3 is associated with renal tubular acidosis, cerebral calcification (marble brain disease) and in some cases with mental retardation.[1] [2] [3] [4] [5] Function[CAH2_HUMAN] Essential for bone resorption and osteoclast differentiation (By similarity). Reversible hydration of carbon dioxide. Can hydrate cyanamide to urea. Involved in the regulation of fluid secretion into the anterior chamber of the eye.[6] [7] Publication Abstract from PubMedAccurate prediction of protein-ligand binding affinities is essential for hit-to-lead optimization and virtual screening. The reliability of scoring functions can be improved by implementing of quantum effects. Here, we demonstrate the ranking power of the semiempirical quantum mechanics (SQM)/implicit solvent (COSMO) scoring function using a challenging set of 10 inhibitors binding to carbonic anhydrase II via Zn2+ in the active site. This new dataset consists of the high-resolution (1.1 - 1.4 A) crystal structures and experimentally determined Ki values. It allowed us to evaluate the common approximations, such as representing the solvent implicitly or using a single target conformation combined with a set of ligand docking poses. The SQM/COSMO attained good correlation of R2 0.56 - 0.77 with the experimental inhibitory activities, benefiting from the careful handling of both noncovalent interactions (e.g. charge transfer) and solvation. This proof-of-concept study of SQM/COSMO ranking for metalloprotein-ligand systems demonstrates its potential for hit-to-lead applications. Ranking Power of the SQM/COSMO Scoring Function on Carbonic Anhydrase II-Inhibitor Complexes.,Pecina A, Brynda J, Vrzal L, Gnanasekaran R, Horejsi M, Eyrilmez S, Rezac J, Lepsik M, Rezacova P, Hobza P, Majer P, Veverka V, Fanfrlik J Chemphyschem. 2018 Jan 8. doi: 10.1002/cphc.201701104. PMID:29316128[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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