Exploring Novel N-Myristoyltransferase Inhibitors: A Molecular Dynamics Simulation Approach

Abstract

N -Myristoyltransferase (NMT) is a cytosolic monomeric enzyme involved in the allocation of the myristoyl group to the aminoterminal of glycine in several viral and eukaryotic cellular proteins. NMT has been validated as a potential drug target against kinetoplastid for parasitic protozoa. A multistep virtual screening protocol based on the pharmacophore modeling, molecular docking, and molecular dynamics simulation was carried out. Initially, Maybridge database was virtually screened via a validated pharmacophore model. The effective pharmacophore models were accompanied with exclusion volumes to improve their receiver operating characteristic curve to identify potential NMT inhibitors. The hits identified as actives based on the 3D-pharmacophore model were evaluated by molecular docking studies. In stepwise screening, six compounds were shortlisted for the dynamic simulation to get insights into their binding mode. In conclusion, this study provides fundamental information about the architecture of the binding site and some crucial residues that may provide insights into the development of new antiparasitic agents.

Insight into the Dual Inhibition Mechanism of Corilagin against MRSA Serine/Threonine Phosphatase (Stp1) by Molecular Modeling

“…After 200 ns simulation, the binding energy between the protein and corilagin was analyzed using the MM-GBSA method. 33 − 35 The MM-GBSA method can be summarized as follows where Δ E MM is composed of van der Waals (Δ E vdw ), the electrostatic (Δ E ele ), and internal energy (Δ E internal ). Moreover, Δ G sol can be divided into the polar (Δ G GB ) and nonpolar contributions (Δ G NP ), as shown in 3 At the same time, the free energy of the per-residue can be calculated using the MM-GBSA method.…”

QSAR and Pharmacophore Modeling of Nitrogen Heterocycles as Potent Human N-Myristoyltransferase (Hs-NMT) Inhibitors

“…N- myristoyltransferase (NMT) or glycylpeptide N- tetradecanoyltransferase is an important cellular monomeric enzyme with a crucial role in the growth of various organisms and cellular proliferation [ 1 , 2 , 3 , 4 , 5 ]. It is ubiquitously distributed, which follows a sequentially ordered bi-bi mechanism to accomplish protein N- myristoylation [ 2 , 4 , 5 ].…”

“…N- myristoyltransferase (NMT) or glycylpeptide N- tetradecanoyltransferase is an important cellular monomeric enzyme with a crucial role in the growth of various organisms and cellular proliferation [ 1 , 2 , 3 , 4 , 5 ]. It is ubiquitously distributed, which follows a sequentially ordered bi-bi mechanism to accomplish protein N- myristoylation [ 2 , 4 , 5 ]. The process of protein N- myristoylation is a two-step process which involves catalytic irreversible shifting of the myristoyl group to the N- terminal glycine residue of a number of substrate proteins [ 1 , 2 , 4 , 6 , 7 , 8 ].…”

“…It is ubiquitously distributed, which follows a sequentially ordered bi-bi mechanism to accomplish protein N- myristoylation [ 2 , 4 , 5 ]. The process of protein N- myristoylation is a two-step process which involves catalytic irreversible shifting of the myristoyl group to the N- terminal glycine residue of a number of substrate proteins [ 1 , 2 , 4 , 6 , 7 , 8 ]. It is a co- and post-translational modification resulting in increased protein lipophilicity, facilitates membrane localization, and optimizes binding with cellular membranes proteins and several lipophilic proteins [ 4 , 5 ].…”

“…It is a co- and post-translational modification resulting in increased protein lipophilicity, facilitates membrane localization, and optimizes binding with cellular membranes proteins and several lipophilic proteins [ 4 , 5 ]. It has been established that in cancerous states, the expression of NMT activity increases significantly in human adenocarcinoma, gallbladder cancer, and different types of cancers [ 1 , 2 , 3 , 4 , 5 , 6 ]. Similarly, the proliferative capacity is found to be linked with NMT activity in mammary epithelial cells, thereby making it a suitable target for cancer therapy.…”