Quantum chemical study on the interaction of some bisphosphonates and Ca2+: The role of molecular electrostatic potentials in the prediction of binding geometry

SummaryMolecular electrostatic potentials have been used to model the calcium binding properties of some bisphosphonate drugs, which are used to treat various bone diseases. The mechanism of action involves the binding of bisphosphonates to the bone surface, where calcium plays an important role. Electrostatic potential maps derived from ab initio partial charges have been compared with both the crystal structure and the fully optimized ab initio structure of (dichloro)methylenebisphosphonate-calcium ion complex. Molecular electrostatic potentials can correctly predict the calcium binding geometry of bisphosphonate-type compounds and this type of information can be used in the practical drug design work.

[1]  P. Dean,et al.  Molecular Foundations of Drug-Receptor Interaction , 1987 .

[2]  Andrew Streitwieser,et al.  Molecular orbital theory for organic chemists , 1961 .

[3]  L. Pedersen,et al.  INteraction of calcium and magnesium ions with malonate and the role of the waters of hydration. A quantum mechanical study , 1991 .

[4]  B. Pullman,et al.  Electronic structure of the α-amino acids of proteins , 1963 .

[5]  J A McCammon,et al.  Computer-aided molecular design. , 1987, Science.

[6]  Y. Martin,et al.  Quantitative drug design , 1978 .

[7]  J. Gasteiger,et al.  ITERATIVE PARTIAL EQUALIZATION OF ORBITAL ELECTRONEGATIVITY – A RAPID ACCESS TO ATOMIC CHARGES , 1980 .

[8]  Ralph E. Christoffersen,et al.  Computer-assisted drug design , 1979 .

[9]  L. Pedersen,et al.  An ab initio mo study of calcium and magnesium complexes with malonate and formate , 1985 .

[10]  David W. Christianson,et al.  Stereochemistry of phosphate-Lewis acid interactions: implications for nucleic acid structure and recognition , 1990 .

[11]  H. Fleisch,et al.  Diphosphonates Inhibit Formation of Calcium Phosphate Crystals in vitro and Pathological Calcification in vivo , 1969, Science.

[12]  R. S. Mulliken.  Electronic Population Analysis on LCAO–MO Molecular Wave Functions. I , 1955 .

[13]  J. G. Vinter,et al.  Strategic approaches to drug design. I. An integrated software framework for molecular modelling , 1987, J. Comput. Aided Mol. Des..

[14]  Y. Martin,et al.  A practitioner's perspective of the role of quantitative structure-activity analysis in medicinal chemistry. , 1981, Journal of medicinal chemistry.

[15]  W. Hehre,et al.  Molecular orbital theory of the properties of inorganic and organometallic compounds 4. Extended basis sets for third‐and fourth‐row, main‐group elements , 1986 .

[16]  M. Nardelli,et al.  A structural study of metal binding of gem-diphosphonates, bone growth regulators , 1983 .

[17]  Giuseppe Del Re,et al.  812. A simple MO–LCAO method for the calculation of charge distributions in saturated organic molecules , 1958 .

[18]  Y. Shiratori,et al.  Parametrization of calcium binding site in proteins and molecular dynamics simulation on phospholipase A2 , 1991 .