Molecular Docking Investigation of the Binding Interactions of Macrocyclic Inhibitors with HCV NS3 Protease and its Mutants (R155K, D168A and A156V)

Abstract

Hepatitis C Virus (HCV) non-structural protein 3 (NS3) protease drug resistance poses serious challenges on the design of an effective treatment. Substrate Envelope Hypothesis, "the substrates of HCV NS3/4A protease have a consensus volume inside the active site called substrate envelope" is used to design potent and specific drugs to overcome this problem. Using molecular docking, we studied the binding interaction of the different inhibitors and protein and evaluated the effect of three different mutations (R155K, D168A and A156V) on the binding of inhibitors. P2-P4 macrocycles of 5A/5B and modified 5A/5B hexapeptide sequences have the best scores against the wild-type protein -204.506 and -206.823 kcal/mole, respectively. Also, charged P2-P4 macrocycles of 3/4A and 4A/4B hexapeptide sequences have low scores with the wild-type protein -200.467 and -203.186 kcal/mole, respectively. R155K mutation greatly affects the conformation of the compounds inside the active site. It inverts its orientations, and this is because the large and free side chain of K155 which restricts the conformation of the large P2-P4 macrocycle. The conformation of charged P2-P4 macrocycle of 3/4A hexapeptide sequence in wild-type, A156V and D168A proteins is nearly equal; while that of charged P2-P4 macrocycle of 4A/4B hexapeptide sequence is different. Nevertheless, these compounds have a slight increase of Van der Waals volume compared to that of substrates, they are potent against mutations and have good scores. Therefore, the suggested drugs can be used as an effective treatment solving HCV NS3/4A protease drug resistance problem.

Conformational Transition Pathway in the Inhibitor Binding Process of Human Monoacylglycerol Lipase

“…4 (C i = OÁÁÁH-N i?4 ). The hydrogen bond contacts were characterized by percentage of occurrence data [30][31][32]. The analysis indicated that the…”

Evaluating Andrographolide as a Potent Inhibitor of NS3-4A Protease and Its Drug-Resistant Mutants UsingIn SilicoApproaches

“…The structures thus obtained were optimized classically using CHARMm force field implemented in the DS 3.5, minimized with conjugate gradient energy minimization protocol followed by convergence energy minimization (0.001 kcal/mole), that readied the structures for docking and simulations [ 24 ]. Active site residues ( Q41, F43, H57, G58, D81, R109, K136, G137, S138, S139, G140, G141, F154, R155, A156, A157, D168, M485, V524, Q526, and H528 ) [ 25 ] were selected for both the wild-type protein and mutant structures for molecular docking studies.…”

Novel inhibitors against wild-type and mutated HCV NS3 serine protease: an in silico study

“…The mutated proteins are geometrically optimized using the MM3 force field. The NS3 serine protease mutations are as follows: A156S, A156T, A156V, D168A, D168E, D168G, D168I, D168V, F43S, Q41R, R155K, R155Q, S138T, T54A, T54S, V36A, V36G, V36L and V36M [12,25].…”

“…Docking calculations are performed using the default docking options for SCIGRESS 3.0 software installed on a Dell Precision T3500 workstation. The ligands and active site residues are flexible to allow the molecular arrangements that occur during recognition and binding [12]. The Potential Mean Force (PMF04) [18] scoring function is utilized with a grid spacing of 0.25.…”