Mohd. Athar, Mohsin Yousuf Lone, Vijay M. Khedkar, Ashish Radadiya, Anamik Shah and Prakash C. Jha
Vinca domain of tubulin protein is a potent binding domain for various microtubule targeting drugs (MTD). However, binding mechanism and structure-activity-relationship (SAR) of this domain is not well understood in terms of ligand-receptor interactions and structure functionality requirements. Possibly, this limits the exploitation of this domain for developing novel clinical leads. Therefore, any step towards modelling and comprehension is of central contour. With this objective, we present here an In-silico insight through the development of a robust pharmacophore model and SAR analysis on a set of 26 well known Vinca domain binders of tubulin protein. The predictive 3D-QSAR based pharmacophore model consists of two hydrogen bond acceptors (A), two hydrogen bond donors (D) and one hydrophobic (H) group with discrete geometries as pharmacophoric features was developed from the dataset. The statistically significant model (r2 = 0.98, q2 = 0.72, F = 562.9, RMSE = 0.11 and Pearson-R = 0.87) was subsequently employed as 3D search query to screen ZINC drug-like database in order to obtain novel scaffolds. To reﬁne the retrieved hits and for gauzing their affinity towards the tubulin protein, docking experiments were taken into account. Furthermore, molecular dynamics simulations were performed to assess the conformational stability and interactions integrity of the protein-ligand complex. In a nutshell, the rendered hit molecules could serve as potential inhibitory leads for the development of improved inhibitors targeting Vinca domain.
pharmacophore, microtubules, antimitotic, virtual screening, Natural products, Molecular Docking, QSAR
School of Chemical Sciences, Central University of Gujarat, Gandhinagar 382030, Gujarat, School of Chemical Sciences, Central University of Gujarat, Gandhinagar 382030, Gujarat, School of Health Sciences, Discipline of Pharmaceutical Sciences, University of KwaZulu-Natal,Westville, Durban 4000, Department of Chemistry, Saurashtra University, Rajkot 360005, Gujarat, Department of Chemistry, Saurashtra University, Rajkot 360005, Gujarat, Centre for Applied Chemistry, Central University of Gujarat, Gandhinagar 382030, Gujarat