In Silico Optimized Mechlorethamine Based Drug Structures Targeting Brain and Spinal Cord Tumors.

ABSTRACT

Aims: Brain and spinal cord tumors are the third most common type of childhood cancer following leukemia and lymphoma. Mechlorethamine (or mustine) is a nitrogen mustard antineoplastic drug. Eleven variants of mechlorethamine are presented that possess molecular properties enabling substantial access to tumors of the central nervous system. Study Design: An extensive in silico search within a data library of molecular structures identifieddrug scaffolds suitable for targeting brain tumors. Place and Duration of StudyUniversity of Nebraska, Durham Science Center, Department of Chemistry, Omaha, Nebraska 68182 USA, between July 2012 to December 2012. Methodology: Following extensive in silico search and identification of potential drug structures, a conclusive set of brain penetrating structures were compiled. Extensive characterization of structure properties was accomplished followed by multivariate numerical analysis utilizing pattern recognition and statistical analysis. Results: All twelve compounds (including mechlorethamine) exhibited zero violations of Rule of 5, indicating favorable bioavailability. The range in Log P, formula weight, and polar surface area for these compounds are 1.554 to 3.52, 156.06 to 324.12, and 3.238 A2to 22.24A2,respectively. High resolution hierarchical cluster analysis determined that agent 2 and 6 are most similar to the parent compound mechlorethamine. The average Log P, formula weight, polar surface area, and molecular volume are 2.446, 235.433, 8.58 A2, and 213.8 A3, respectively. Conclusion: These eleven drug designs possess attributes that effectuate high permeation into the central nervous system.