Molecular relaxation: This concept takes one step further toward accounting
protein flexibility from side chain rotation. In this approach, ligand is docked in the
binding site of the receptor allowing potential atomic overlaps to certain extent
followed by relaxation stage where docked pose of the ligand is energy minimized
and complex is relaxed allowing backbone relaxation along with side chain using
molecular dynamics or Monte Carlo simulation. Apostolakis et al. performed a
study in which they tried to incorporate receptor flexibility to model induced fit in
ligand and binding site over three challenging docking cases: (i) anti-steroid
antibody DB3 with two ligands, a rigid-ligand progesterone (no rotatable bonds)
and (ii) a flexible-ligand 5b–androstane-3,17-dione (having rotatable bonds), and
(iii)
N
a -(2-naphthyl-sulfonyl-glycyl)-D-para-amidino-phenyl-alanyl-piperidine
(NAPAP) binding to human a-thrombin [87]. Progesterone and 5b-androstane3,17-dione show two different binding modes, thus make a perfect test case. In this
method, ligand was seeded to the center of binding pocket in random pose followed
by a combination of minimization with shifted non-bonded interaction and Monte
Carlo minimization; authors were able to successfully reproduce the crystalized
pose for test cases with native structure of protein and without prior knowledge of
structure of NAPAP in a-thrombin case [87]. This study highlighted the importance
of considering receptor flexibility under the influence of ligands interaction field in
docking. Davis and Baker [88] implemented a method in ROSETTALIGAND to
account for the receptor backbone flexibility along with full-ligand flexibility and
showed that on a challenging cross-docking test case of Meiler and Baker [89] (10
co-crystallized receptor–ligand pairs, with large flexible ligands and multiple side
chains with changing rotamer), their new method reproduces binding poses better
(lower RMSD for best-scoring docked poses) in comparison to their rigid-backbone
docking.
Multiple structure docking: McCammon and co-workers [90] used relaxed complex method to dock fully flexible version of prospective drug molecules JE-2147
wild-type and V82F/I84V drug-resistant mutants of HIV-1 protease ensemble of
conformations. In both cases, wild-type and mutant HIV-1 protease, an ensemble of
2200 conformation from 22 ns all atom explicit solvent MD simulation of closed
conformers of apo structures of receptor and coordinates were saved every 10 ps; in
both cases, crystal structure poses were successfully reproduced. Later, JE-2147 was
docked to each 2200 conformation for both wild-type and mutant cases and optimized the protocol. To synthesize test inhibitors, same protocol was applied to dock
23 newly designed potential inhibitor (called JE.D.I. series molecules) to 700 conformations of the HIV-1 protease mutant. Based on high binding free energy of four
compounds of the JE.D.I., which were significantly different from their parent
compound JE-2147 as well rest members of the series; four new compounds with
potentially better pharmacological properties were suggested for test [90].
Similar concept but using MD simulation to dock and identify the interactions
between domain motions to influence the inhibitor/ligand binding has been
attempted in case of Fe-artemisinin adduct binding to PfATP6, a Ca
++ transporter
well-known target in Plasmodium falciparum [91].
In Silico Structure-Based Prediction of Receptor–Ligand Binding …
125
protein flexibility from side chain rotation. In this approach, ligand is docked in the
binding site of the receptor allowing potential atomic overlaps to certain extent
followed by relaxation stage where docked pose of the ligand is energy minimized
and complex is relaxed allowing backbone relaxation along with side chain using
molecular dynamics or Monte Carlo simulation. Apostolakis et al. performed a
study in which they tried to incorporate receptor flexibility to model induced fit in
ligand and binding site over three challenging docking cases: (i) anti-steroid
antibody DB3 with two ligands, a rigid-ligand progesterone (no rotatable bonds)
and (ii) a flexible-ligand 5b–androstane-3,17-dione (having rotatable bonds), and
(iii)
N
a -(2-naphthyl-sulfonyl-glycyl)-D-para-amidino-phenyl-alanyl-piperidine
(NAPAP) binding to human a-thrombin [87]. Progesterone and 5b-androstane3,17-dione show two different binding modes, thus make a perfect test case. In this
method, ligand was seeded to the center of binding pocket in random pose followed
by a combination of minimization with shifted non-bonded interaction and Monte
Carlo minimization; authors were able to successfully reproduce the crystalized
pose for test cases with native structure of protein and without prior knowledge of
structure of NAPAP in a-thrombin case [87]. This study highlighted the importance
of considering receptor flexibility under the influence of ligands interaction field in
docking. Davis and Baker [88] implemented a method in ROSETTALIGAND to
account for the receptor backbone flexibility along with full-ligand flexibility and
showed that on a challenging cross-docking test case of Meiler and Baker [89] (10
co-crystallized receptor–ligand pairs, with large flexible ligands and multiple side
chains with changing rotamer), their new method reproduces binding poses better
(lower RMSD for best-scoring docked poses) in comparison to their rigid-backbone
docking.
Multiple structure docking: McCammon and co-workers [90] used relaxed complex method to dock fully flexible version of prospective drug molecules JE-2147
wild-type and V82F/I84V drug-resistant mutants of HIV-1 protease ensemble of
conformations. In both cases, wild-type and mutant HIV-1 protease, an ensemble of
2200 conformation from 22 ns all atom explicit solvent MD simulation of closed
conformers of apo structures of receptor and coordinates were saved every 10 ps; in
both cases, crystal structure poses were successfully reproduced. Later, JE-2147 was
docked to each 2200 conformation for both wild-type and mutant cases and optimized the protocol. To synthesize test inhibitors, same protocol was applied to dock
23 newly designed potential inhibitor (called JE.D.I. series molecules) to 700 conformations of the HIV-1 protease mutant. Based on high binding free energy of four
compounds of the JE.D.I., which were significantly different from their parent
compound JE-2147 as well rest members of the series; four new compounds with
potentially better pharmacological properties were suggested for test [90].
Similar concept but using MD simulation to dock and identify the interactions
between domain motions to influence the inhibitor/ligand binding has been
attempted in case of Fe-artemisinin adduct binding to PfATP6, a Ca
++ transporter
well-known target in Plasmodium falciparum [91].
In Silico Structure-Based Prediction of Receptor–Ligand Binding …
125