Per-residue energy decomposition pharmacophore model to enhance virtual screening in drug discovery: a study for identification of reverse transcriptase inhibitors as potential anti-HIV agents

Figures & data

Figure 1 Ribbon representation of HIV-1 RT-GSK952 complex.

Note: HIV-1 RT-GSK952 complex (PDB code 2YNI) with finger (blue), palm (magenta), thumb (cyan), connection (forest green) and RNase H (orange red) of p66 subunit and GSK952 (green).
Abbreviations: RT, reverse transcriptase; PDB, Protein Data Base.

Figure 2 The 2D structure of ligand GSK952 used to generate the pharmacophore model.

Abbreviation: 2D, two dimensional.

Figure 3 A schematic representation of the VS workflow used in the current study.

Abbreviations: VS, virtual screening; PDB, Protein Database; MD, molecular dynamic; MMPBSA, molecular mechanics/Poisson–Boltzmann surface area; PRED, per-residue energy decomposition; HCAAR, highly contributing amino acid residues; FBE, free binding energy.

Figure 4 A diagrammatic representation of the pharmacophore model.

Notes: (A) PRED contributions, (B) 2D ligand interaction plot, and (C) pharmacophore features responsible for FBE contributions.
Abbreviations: PRED, per-residue energy decomposition; FBE, free binding energy; vdW, van der Waals; Elec, electrostatic; 2D, two dimensional.

Table 1 Validation of molecular docking approach

Compound number	Compound code	DS (kcal/mol)	IC50 (nM)
1	3M8Q	−8.8	0.6
2	2BAN	−8.4	1
3	3IRX	−9.2	1
4	2RF2	−7.9	3.5

Abbreviations: DS, docking score; IC₅₀, half maximal inhibitory concentration.

Figure 5 Validation of molecular docking: docking score vs half maximal inhibitory concentration (IC₅₀).

Table 2 Representation of the top ten compounds displaying 3D shapes, HBD, HBA, xlogP, MW, and calculated DS and RB

Zinc ID	2D structure	xlogP	DS	HBA	HBD	MW	RB
ZINC15175251		4.79	−12.4	6	0	344.32	5
ZINC60349595		5.17	−12.3	6	0	358.35	5
ZINC07980692		5.17	−12.3	6	0	358.35	5
ZINC04952707		3.90	−12.0	7	0	397.40	6
ZINC09490236		4.07	−11.9	5	1	361.42	5
ZINC00868209		5.43	−11.7	6	0	375.3	7
ZINC60462497		3.90	−11.7	7	0	397.40	6
ZINC46849657		4.72	−11.6	8	0	467.53	5
ZINC54359621		−1.62	−11.6	3	0	317.34	4
ZINC89797911		4.07	−11.5	5	1	361.42	5

Abbreviations: 3D, three dimensional; HBD, hydrogen bond donor; HBA, hydrogen bond acceptor; MW, molecular weight; DS, docking score; 2D, two dimensional; RB, rotatable bond.

Table 3 A comparison of GSK952’s binding affinity with that of the top two hits ZINC54359621 and ZINC46849657

Ligand	ΔTotal	ΔEvdW	ΔEelec	ΔGbind	ΔGgas	ΔGsolv
GSK952	−58.8	−61.2	−21.4	30.9	−82.6	23.8
ZINC46849657	−58.5	−67.1	−21.0	37.1	−88.1	29.6
ZINC54359621	−59.0	−67.6	−20.2	36.4	−87.9	28.8

Abbreviations: vdW, van der Waals; elec, electrostatic; solv, solvation.

Figure 6 The per residue graphs showing FBE contribution for both ZINC54359621 and ZINC46849657.

Notes: (A) Top hit 1, ZINC54359621 with the highest total binding energy. (B) Top hit 2, ZINC46849657 with the second highest total binding energy.
Abbreviations: FBE, free binding energy; vdW, van der Waals; Elec, electrostatic.

Figure 7 Binding mode of compounds.

Notes: (A) ZINC54359621 and (B) ZINC46849657 to HIV-1 RT enzyme, respectively.
Abbreviation: RT, reverse transcriptase.

Figure S1 Two key binding interactions exist between GSK952 and the backbone NH and C=O groups of Lys103 of HIV-1 RT.

Abbreviation: RT, reverse transcriptase.

Figure S2 PRED-based pharmacophore model.

Abbreviations: PRED, per-residue energy decomposition; HPI, hydrophobic interaction; HA, hydrogen acceptor.

Figure S3 MD simulation results of ZINC54359621 and ZINC46849657.

Notes: (A) RMSD (average of 3.12 Ǻ and 2.58 Ǻ, respectively), (B) RMSF (average of 1.87 Ǻ, and 1.53 Ǻ, respectively), and (C) Rg (average of 51.2 Ǻ and 51.2 Ǻ, respectively).
Abbreviations: MD, molecular dynamic; RMSD, root-mean-square deviation; RMSF, root-mean-square fluctuation; Rg, radius of gyration.

Table S1 PRED of highly interacting residues

Residue number	Highly interacting residues	FBE (kcal/mol)
1	Val106	−3.556
2	Lys103	−3.311
3	Tyr188	−3.144
4	Lys102	−2.243
5	Leu100	−2.057
6	Phe227	−1.879

Abbreviations: PRED, per-residue energy decomposition; FBE, free binding energy.