Target‐based virtual screening, computational multiscoring docking and molecular dynamics simulation of small molecules as promising drug candidate affecting kinesin‐like protein KIFC1

Abstract

The kinesin family member C1 (KIFC1) is an essential protein that facilitates the bipolar division of neoplastic cells. Inhibiting KIFC1 by small molecules is a lucrative strategy to impede bipolar mitosis leading to the apoptosis of cancerous cells. The research aims to envisage small‐molecule inhibitors targeting KIFC1. The Mcule database, a comprehensive online digital platform containing more than five million chemical compounds, was used for structure‐based virtual screening (SBVS). Druglikeness filtration sifted 2,293,282 chemical hits that further narrowed down to 49 molecules after toxicity profiling. Finally, 39 compounds that comply with the BOILED‐Egg permeation predictive model of the ADME rules were carried forward for multiscoring docking using the AutoDock Vina inbuilt to Mcule drug discovery platform, DockThor and SwissDock tools. The mean of ΔG terms produced by docking tools was computed to find consensus top ligand hits. AZ82 exhibited stronger binding (Consensus ΔG: −7.99 kcal mol−1) with KIFC1 among reference inhibitors, for example, CW069 (−7.57 kcal mol−1) and SR31527 (−7.01 kcal mol−1). Ten ligand hits namely, Mcule‐4895338547 (Consensus ΔG: −8.69 kcal mol−1), Mcule‐7035674888 (−8.42 kcal mol−1), Mcule‐5531166845 (−8.53 kcal mol−1), Mcule‐3248415882 (−8.55 kcal mol−1), Mcule‐291881733 (−8.41 kcal mol−1), Mcule‐5918624394 (−8.44), Mcule‐3470115427 (−8.47), Mcule‐3686193135 (−8.18 kcal mol−1), Mcule‐3955355291 (8.09 kcal mol−1) and Mcule‐9534899193 (−8.01 kcal mol−1) depicted strong binding interactions with KIFC1 in comparison to potential reference inhibitor AZ82. The top four ligands and AZ82 were considered for molecular dynamics simulation of 50 ns duration. Toxicity profiling, physicochemical properties, lipophilicity, solubility, pharmacokinetics, druglikeness, medicinal chemistry attributes, average potential energy, RMSD, RMSF, SASA, ΔGsolv and Rg analyses forecast the ligand mcule‐4895338547 as a promising inhibitor of KIFC1.

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