Development of Efficient Drug Analogs for Dutasteride through Insilico Modeling

Abstract

Action of drug depends on the quantity of drug that reaches to the receptor and the degree of affinity between drug and receptor. Once drug bound to its receptor, it shows its desired effect (intrinsic activity) along with major and minor side-effects. More than 500 drugs with significant side-effects are available in market. In the present study the efforts have been made to identify new candidate compounds for dutasteride through modeled structure of two existing drug targets to improve efficacy by optimizing various parameters. Three dimensional structures of both drug targets of dutasteride were generated by MODELLER, validated by PROCHECK and ERRAT programs (90.04% of model-I and 84.647% of model-II). Energy minimization and molecular dynamics calculations were done through GROMACS using OPLS force field. RMSD calculated for both simulated model attain a constant deviation within 10,000 cycles. For analog generation, mono-substitution is preferred instead of multisubstitution. Objective and subjective both approaches were used for identification and calculation of chemical descriptors. A comparison of the calculated binding affinities for structurally similar inhibitors of dutasteride gave suitable analogs. Total 169 analogs were generated and eight are selected for comparative study. Our finding reveals that three dutasteride drug analogs (CH2NH2, -CH2OH, -CF2OH) were most suitable analogs, showing theoretically more superior results. These findings need to be further evaluations in laboratory.