Consensus Virtual Screening Protocol Towards the Identification of Small Molecules Interacting with the Colchicine Binding Site of the Tubulin‐microtubule System

Abstract

Modification of the tubulin‐microtubule (Tub‐Mts) system has generated effective strategies for developing different treatments for cancer. A huge amount of clinical data about inhibitors of the tubulin‐microtubule system have supported and validated the studies on this pharmacological target. However, many tubulin‐microtubule inhibitors have been developed from representative and common scaffolds that cover a small region of the chemical space with limited structural innovation. The main goal of this study is to develop the first consensus virtual screening protocol for natural products (ligand‐ and structure‐based drug design methods) tuned for the identification of new potential inhibitors of the Tub‐Mts system. A combined strategy that involves molecular similarity, molecular docking, pharmacophore modeling, and in silico ADMET prediction has been employed to prioritize the selections of potential inhibitors of the Tub‐Mts system. Five compounds were selected and further studied using molecular dynamics and binding energy predictions to characterize their possible binding mechanisms. Their structures correspond to 5‐[2‐(4‐hydroxy‐3‐methoxyphenyl) ethyl]‐2,3‐dimethoxyphenol (1), 9,10‐dihydro‐3,4‐dimethoxy‐2,7‐phenanthrenediol (2), 2‐(3,4‐dimethoxyphenyl)‐5,7‐dihydroxy‐6‐methoxy‐4H‐1‐benzopyran‐4‐one (3), 13,14‐epoxyparvifoline‐4’,5’,6’‐trimethoxybenzoate (4), and phenylmethyl 6‐hydroxy‐2,3‐dimethoxybenzoate (5). Compounds 1–3 have been associated with literature reports that confirm their activity against several cancer cell lines, thus supporting the utility of this protocol.

Putative mechanism of a multivitamin treatment against insulin resistance

“…Using the ‘Triangle Matcher’ method, the binding compounds were subjected to 50 search steps (poses) and the default values for the other parameters. Clusters with RMSD < 2 Å were visually explored and considered representative and potential interactions against the studied targets [ 83 ]. During docking simulations, the receptor was considered rigid, and the ligands were flexible.…”

Exploring activity landscapes with extended similarity: is Tanimoto enough?

“…For example, toxicity and side effects. Also, it is possible to use this index to develop consensus (or fused) similarity metrics that have demonstrated extensive applicability in drug design and discovery [40,41].…”

Exploring activity landscapes with extended similarity: is Tanimoto enough?

“…Also, it is possible to use this index to develop consensus (or fused) similarity metrics that have demonstrated extensive applicability in drug design and discovery. 40,41…”