Exploration of Structure Activity Relationship Using Integrated Structure and Ligand Based Approach: Hydroxamic Acid Based HDAC inhibitors and Cytotoxic Agents

INTRODUCTION: The present study aimed to establish significant and validated quantitative structure activity relationship (QSAR) models for HDAC inhibitors and correlate their physicochemical, steric, and electrostatic properties with their anti-cancer activity.
METHODS: We have selected a dataset from the earlier research findings. The target and ligand molecules were procured from recognized databases, were incorporated into pivotal findings such as molecular docking (XP Glide), e-pharmacophore study and 3D QSAR model designing study (Phase).
RESULTS: The docking studies revealed molecule 39 with better docking score and well binding contact with protein. The significant interaction between ligand and receptor were (i) metallic bond interaction with Zinc (Zn2451) of receptor 1ZZ1 and keto group of ligand (ii) hydrogen bond formation between NH- moiety of hydroxamic acid group of ligand with GLY151 and TYR312 amino acids (iii) Hydrogen bonding is also visible between NH- moiety of indole ring and ASP98 amino acid (iv) hydrophobic interaction of PHE208 with five membered ring B of indole and benzene ring of compound 39.The 3D QSAR analysis performed for PLS factor 5, reported good 0.9877 and 0.7142 as R2and Q2values, respectively and low standard of deviation SD = 0.1049 for hypothesis AADRR.139.
DISCUSSION AND CONCLUSION: Based on the computational outcome, it has been concluded that molecule 39 is an effectual and relevant candidate for inhibition of HDAC activity. Moreover, these computational approaches motivate to discover novel drug candidates in the pharmacological and healthcare sectors.