DRUG LIKE FILTERS AND MOLECULAR DYNAMICS AS A TOOL IN RATIONAL DRUG DESIGN: APPLICATION TOWARDS BIOACTIVE ANALGESIC PEPTIDE LEADS
Kandasamy Nagarajan, Nitesh Chauhan, Dhananjay Sharma, Nishant Chaudhary, Manoj Kumar, Pritesh Kumar · 2012
The main objective of our rational drug design is to predict the best novel shorter chain peptide leads for analgesic effect from the designed set of templates with various descriptors such as Boman index, lipinski rules and molecular dynamics simulations. We built sixty five candidate molecules (20 tripeptides; 45 tetrapeptides) from chemical templates and subjected to Boman index through online antimicrobial peptide database. The best resulting eighteen templates (3 tripeptides; 15 tetrapeptides) derived from this database were passed them through empirical lipinski filters to assess drug like properties using various molecular descriptors namely molecular mass, partition coefficient, Hydrogen bond donors and Hydrogen bond acceptors respectively. Later, we conducted molecular dynamics on the best resulting templates with twenty nano second simulations of total atoms at an average temperature 298.15K in hundred steps with applying constraints to all bonds in pure water. Finally, the conformational stability of the candidates were analyzed with measurement of Total potential energy, Total Kinetic energy, Bond stretch energy, Bond angle bending energy, Torsion angle energy, Restraining torsional energy and Hydrogen bond energy. In addition, the protein–ligand binding was tested with Lennard jones energy and Electrostatic energy for all the best templates. Among the results obtained with molecular dynamics for various non–bonded interactions, we identified Phe-Lys-Gln-Tyr (FKQY), Phe-Trp-Lys-Tyr (FWKY), Phe-His-Arg-Tyr (FHRY) and Met-Met-Phe-Tyr (MMFY) as potent tetrapeptide leads with maximum conformational stability for analgesic effect among the selected sixty five template sets.