Complex modeling of drug structure-cellular effects using CoMFA-QSAR data.

Rajesh J. Oswal ( oswal_rajesh-AT-rediffmail-DOT-com.gif ), Shivajirao S. Kadam
Department of Pharmaceutical and Medicinal Chemistry, Bharati Vidyapeeth Deemed University, Erandwane, PUNE - 411038. INDIA.

We made an attempt to develop validated models and software, based upon physical chemical principles, which predict the bound conformations of noncovalent complexes and their standard free energies of binding. Such models will be of value in a range of applications, including protein-engineering, and structure-based drug-design. A novel method of computing configuration integrals forms the basis of our approach to computing binding affinities, and we are also developing novel protein-ligand "docking" algorithms.

We followed rational design, synthesis and biological evaluation of potent and selective small molecules for their binding to the GABA-BZD receptor. Analysis of these molecules in various animal studies and superimposition transformation study with templet Diazepam is carried out routinely to understand their mode of binding with the transporter molecules and to develop a Structure-Activity Relationship studies. Our goal is to explore the potential use of these compounds as medicating agents for the treatment of related GABA related neurological disorders. Further development of Single Photo Electron Computer Tomography (SPECT) and Positron Emission Tomography (PET) agents for imaging studies in the CNS, and also affinity and photo-affinity ligands as molecular probes to characterize the receptor further at the molecular level to understand more of its functional properties is in process.

From first series of compounds results, we were able to demonstrate and identify the pharmacophoric requirement in novel GABAnergic compounds that affords their potent and selective binding to the GABA-BZD receptor. Using rational drug design approach, conformationally constrained versions of our active flexible analogues and observed interesting isomeric selectivity for their biological activity. Currently we are in the process of expanding our SAR studies to generate suitable compounds that will be used in further in vivo studies to develop single drug medication for epilepsy.