Table 3.

Ligand- and pharmacophore-based drug design methodologies reported for ligands targeting GPCRs potentially involved in PD.

Dopamine D2 Receptor (D2R) Agonists
Entry	Method(s)	Ligand(s)				Results/Conclusions
1	CoMFA using SYBYL 6.8 QSAR module [434]	Aminoindans, aminotetralins, dopamine analogs, ergolines, apomorphine, phenylpiperidines, benzo[f]quinolines				CoMFA maps showed that bulky substituents with low electronegativity on the fused piperidine ring nitrogen and small substituents with low electronegativity on the aromatic ring are favorable features for agonist activity [506].
2	CoMFA and CoMSIA using SYBYL 8.0 [434] and MOE v. 2011.10 [507] programs	(S)-6-((2-(4-Phenylpiperazine-1-yl)-ethyl)(propyl)amino)-5,6,7,8-tetrahydronaphthalene-1-ol analogs				The key features for ligand activity are divided into two groups: near the aminotetralin head group and at/near the phenyl ring bound to piperazine moiety. Near the aminotetralin head group, the presence of bulky groups on 5-methoxy group of aminotetralin moiety is beneficial for activity; the introduction of bulky groups near the N-propyl group of aminotetralin moiety is expected to decrease the activity; the presence of electronegative substituents at 7-position of aminotetralin group and hydrophilic groups near the N-propyl group is predicted to enhance activity; a beneficial effect for activity is also expected upon the introduction of hydrogen bond donor groups near the 5- and 7-positions and near the N-propyl group of aminotetralin moiety. The presence of bulky substituents at 6-, 7-, and 8- positions of quinoline ring, electropositive groups on 3-position, and hydrophilic substituents on quinoline ring is favorable for activity. The introduction of hydrophilic substituents around the piperazine ring and hydrogen bond donor groups on the nitrogen atom of piperazine ring enhances the binding affinity [508].
3	Pharmacophore modeling using Discovery Studio software [416]	Arylpiperazines				Pharmacophore model including key features for ligand activity: (i) salt bridge interactions between the basic nitrogen atom of piperazine ring and the receptor; (ii) one or more aromatic interactions involving arylpiperazine substructure; (iii) hydrogen bond interaction between the oxygen atom of methoxy group and the receptor; (iv) possibility of hydrogen bond interaction involving the linker part [417].
4	Pharmacophore modeling using MOE v. 2005.06 [509]	Aminotetralins, apomorphine, quinolines				Pharmacophore model including key features for ligand activity: (i) one excluded volume covering the projected feature Asp; (ii) one positively charged nitrogen atom interacting with Ser; (iii) one hydrogen bond donor feature interacting with Asp; (iv) one aromatic ring feature [510].
Dopamine D3 Receptor (D3R) Agonists
Entry	Method(s)	Ligand(s)				Results/Conclusions
5	HQSAR and CoMFA using SYBYL 6.6 program [434]	Piperazinylalkylisoxazole analogues				The best HQSAR model was constructed using Atom, Bond, Connectivity, Donor and Acceptor (A/B/C/DA) as fragment type, 257 as hologram length, and 4–7 as fragment size. CoMFA models showed that the electrostatic parameters are the most contributing factor for D3R agonist affinity of these ligands [511].
6	CoMFA using SYBYL-X 1.3 program [434]	Library of 34 structurally diverse D3R agonists				Two representative molecules were used to analyze the key features for D3R binding affinity. N-((1S,4r)-4-(2-(((S)-2-Amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl) amino)ethyl)cyclohexyl)-3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide: (i) the presence of bulky groups near the 2- and 3-position in pyridine ring enhances the binding affinity and near the 4-position of pyridine ring is expected to reduce the activity; (ii) the presence of electropositive groups near the 2-position and electronegative groups near the 4- and 5-position in pyridine ring may enhance activity. N-((1S,4r)-4-(2-(((S)-2-Amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl) amino)ethyl)cyclohexyl)-2-chloropyridine-3-sulfonamide: (i) the introduction of bulky and electronegative substituents near the 5-position of the benzene ring is expected to increase agonist activity; (ii) the introduction of electropositive groups near methyl position of 1,2,4-oxadiazole ring is favorable for activity [424].
7	CoMFA and CoMSIA using SYBYL 7.2 program [434]	Library of 41 structurally diverse D3R agonists				The hydrophobic interactions are the most important contributing factor for D3R agonist activity. Hydrogen bonding also contributes largely to the binding affinity and may confer receptor subtype selectivity [512].
Dopamine D3 Receptor (D3R) Agonists
Entry	Method(s)			Ligand(s)	Results/Conclusions
8	CoMFA and CoMSIA using SYBYL 8.0 [434] and MOE v. 2011.10 [507] programs			(S)-6-((2-(4-Phenylpiperazine-1-yl)-ethyl)(propyl)amino)-5,6,7,8-tetrahydronaphthalene-1-of analogs	The key features for ligand activity are divided into two groups: near the aminotetralin head group and at/near the phenyl ring bound to piperazine moiety. Regarding the aminotetralin head group, the introduction of bulky substituents around 7- and 8-positions, hydrophobic and hydrophilic substituents on phenyl and cyclohexyl rings of aminotetralin moiety, respectively, is favorable for activity. The presence of bulky groups near the N-propyl group of aminotetralin moiety is expected to reduce the binding affinity to D3R. The introduction of both hydrogen bond donor and acceptor substituents near piperazine ring is predicted to be favorable for agonist activity [508].
9	Pharmacophore modeling using Chem-X software			(R)-(+)-PD-128907, (R)-(+)-7-OH-DPAT, BP-897, (S)-(-)-3-PPP, pramipexole, (+)-UH-232, (S)-(-)-DS-121, quinelorane, (-)-quinpirole, ropinirole	Pharmacophore model including common key features for these ligands: (i) one aromatic ring and one sp3 nitrogen bound to a propyl group and to two additional sp3 carbons; (ii) the distance between the aromatic ring center and the basic sp3 nitrogen within these compounds was found to be on approximately 5.16 ± 0.16 Å [419].
Adenosine A2A Receptor (A2AAR) Antagonists
Entry	Method(s)			Ligand(s)	Results/Conclusions
10	HQSAR using SYBYL 7.2 program [434]			2-(Furan-2-yl)-[1,2,4]triazolo[1,5-f]pyrimidin-5-amines, 2-(furan-2-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-amines, 2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amines	The best HQSAR model includes the combination of fragment parameters A/B/C/DA, with a size fragment of 7-10 and a hologram length of 199. The structure features that contribute positively for the activity are: (i) for 2-(furan-2-yl)-[1,2,4]triazolo[1,5-f]pyrimidin-5-amines, the presence of a substituent at C3 of phenyl ring; (ii) for 2-(furan-2-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-amines, a short length of carbon chain between the piperazine moiety and the methylated nitrogen atom [446].
11	CoMFA using SYBYL 6.3 program [434]			Flavonoids	The key features for high affinity to A2AAR are: (i) the presence of bulky substituents at C2, C7, and C8 of chromone ring; (ii) the absence of high electron density groups at the para position of phenyl ring [513].
12	CoMFA using SYBYL-X 1.1.1 program [434]			Substituted thieno[2,3-d]pyrimidines	The key features for A2AAR antagonistic activity are: (i) the presence of bulky substituents in the thiophene ring and small substituents in the pyrimidine ring; (ii) electropositive substituents between positions 1 and 2 and at position 4 of benzene ring located at pyrimidine ring; (iii) electronegative substituents at position 2 of the benzene ring located at the pyrimidine ring [429].
13	CoMFA and CoMSIA using DRAGON software [514]			Pyrimidine and triazine derivatives, pyrazolo[3,4-d]pyrimidines, pyrrolo[2,3-d]pyrimidines, triazolo[4,5-d]pyrimidines, 6-arylpurines, thieno[3,2-d]pyrimidines	For pyrimidine and triazine derivatives, the key features for A2AAR antagonistic activity are: (i) the presence of a limitedly bulky, electronegative, and hydrophobic group at C6; (ii) the presence of a small, electronegative, and hydrophilic group at C2; (iii) a limitedly bulky, electronegative, and hydrophilic group (non hydrogen bond donor group) at C4. For pyrazolo[3,4-d]pyrimidines, pyrrolo[2,3-d]pyrimidines, triazolo[4,5-d]pyrimidines, and 6-arylpurines, the key features for A2AAR antagonistic activity are: (i) the presence of a small, and electronegative group (hydrogen bond acceptor group) at C6; (ii) a hydrogen bond donor group at C2; (iii) a hydrogen bond acceptor group at N3. For thieno[3,2-d]pyrimidines, the key features for A2AAR antagonistic activity are: (i) the presence of a limitedly bulky, electronegative, and hydrophilic group (hydrogen bond donor group) at C6, a small and electronegative group (hydrogen bond donor group) [445].
14	Pharmacophore modeling and GFA-based QSAR using Cerius2 [418] and LigandScout programs [515]			4-Arylthieno[3,2-d]-pyrimidines	Molecular connectivity índex (SC-2), molecular surface area (AREA), graph-theoretical (WIENER), and molecular flexibility (PHI-MAG) descriptors influenced the activity of ligands against A2AAR. Pharmacophore model including key features for ligand activity: (i) the presence of one hydrogen bond donor feature (amino group interacts with Asn253), two hydrophobic features (one group interacts with Leu85, Phe168, Met177, Trp246, and Leu249 residues; other group interacts with Leu269 and Met270 residues) [98].
15	Pharmacophore modeling and QSAR using PHASE 3.2 module of Schrodinger suite [516]			Library of 46 A2AAR antagonists	Pharmacophore model including key features for ligand activity: (i) one hydrogen bond acceptor feature; (ii) one hydrogen bond donor feature; (iii) one hydrophobic feature; (iv) two aromatic ring features [430].
Adenosine A2A Receptor (A2AAR) Antagonists
Entry	Method(s)		Ligand(s)						Results/Conclusions
16	Pharmacophore modeling using CATALYST 4.11 software package [517]		Xanthine derivatives (KW6002, KF17837, BS-DMPX) Non-xanthine derivatives (7-substituted 5-amino-2-(2-furyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines and piperazine derivatives of [1,2,4]triazolo[1,5-a]triazine)						Pharmacophore models for xanthine and non-xanthine derivatives including key features for ligand activity: (i) two hydrophobic features; (ii) one hydrogen bond acceptor feature; (iii) one aromatic ring feature [445].
17	Pharmacophore modeling using PHASE 2.0 module of Schrodinger suite [516]		Library of 68 A2AAR antagonists						Pharmacophore model 1 including key features for ligand activity: (i) two hydrogen bond acceptor features; (ii) two aromatic ring features; (iii) one hydrogen bond donor feature. Pharmacophore model 2 including key features for ligand activity: (i) two hydrogen bond acceptor features; (ii) one hydrogen bond donor feature; (iii) one aromatic ring; (iv) one hydrophobic feature [518].
18	Pharmacophore modeling using CATALYST 4.10 software package [517]		7-Substituted 5-amino-2-(2-furyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines						Pharmacophore model including key features for ligand activity: (i) one ring aromatic feature; (ii) one positively ionizable feature; (iii) one hydrogen bond acceptor lipid feature; (iv) one hydrophobic feature [519].
19	Pharmacophore modeling using CATALYST 4.11 program [517]		1,2,4-Triazole derivatives, pyrazolotriazolopyrimidines, trifluoropyrimidines, 9-ethyladenine derivatives, thioacyhydrazones						Pharmacophore model including key features for ligand activity: (i) one hydrogen bond donor feature; (ii) three hydrophobic features; (iii) one aromatic ring feature [520].
20	Pharmacophore modeling using PHASE module of Schrodinger suite [516]		Library of 751 A2AAR antagonists						Pharmacophore model including key features for ligand activity: (i) one hydrogen bond acceptor feature; (ii) one hydrogen bond donor feature; (iv) two aromatic ring features [521].
21	Pharmacophore modeling using FLAPPharm program [522]		Istradefyline, MSX-2, SYN-115, BIIB014, SCH-442416, ZM-241385, ST-1535, preladenant						Pharmacophore model including key features for ligand activity: (i) three hydrogen bond acceptor features; (ii) one hydrogen bond donor feature; (iii) hydrophobic features. The proposed pharmacophore is predicted to interact Glu169 and Asn253 [523].
22	Pharmacophore modeling using CATALYST 4.11 program [517]		7-Substituted 5-amino-2-(2-furyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines, piperazine derivatives of triazolotriazine and triazolopyrimidines						Pharmacophore model including key features for ligand activity: (i) two hydrophobic features, and one aromatic ring hydrophobic feature for 7-substituted 5-amino-2-(2-furyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines; (ii) one hydrogen bond acceptor feature, two hydrophobic features, and one aromatic ring hydrophobic feature for piperazine derivatives of triazolotriazine and triazolopyrimidines [432].
M1 muscarinic acetylcholine receptor (mAChR1) antagonists / negative allosteric modulators (NAMs)
Entry	Method(s)		Ligand(s)						Results/Conclusions
23	Pharmacophore modeling and 3D-QSAR using CATALYST 4.10 program [517]		α-Substituted 2,2-diphenylpropionates						The stereoelectronic properties including total energies, bond distances, valence angles, torsion angles, HOMO–LUMO energies, reactivity indices, vibrational frequencies of ether and carbonyl moieties, and nitrogen atom proton influences the binding affinity of these ligands. Pharmacophore model including key features for ligand activity: (i) one aromatic ring feature; (ii) one hydrogen bond donor; (iii) basic nitrogen species at a distance of ~4Å from the hydrogen bond acceptor [524].
24	Pharmacophore modeling using PHASE module of Schrodinger suite [516]		Trihexylphenidyl, atropine, darifenacin, 4-DAMP, propantheline, pirenzepine						Pharmacophore model including the common molecular features: (i) molecular weight: 289.37–426.55; (ii) polar surface area: 23.47–68.78 Å2; (iii) hydrogen bond acceptors: 1–3; (iv) hydrogen bond donors: 0–1; (v) rotatable bonds: 2–7; (vi) AlogP: 1.68–4.53 [525].
25	Pharmacophore modeling using CATALYST 4.10 program [517]		Caramiphen, indocaramiphen, nitrocaramiphen, atropine, dicyclomine, methoctramine, oxybutynin						Pharmacophore model including key features for ligand activity: (i) two hydrogen bond acceptor features; (ii) one aliphatic hydrophobic feature; (iii) one aromatic ring feature [526].
Metabotropic Glutamate Receptor 4 (MGluR4) agonists / positive allosteric modulators (PAMs)
Entry	Method(s)		Ligand(s)						Results/Conclusions
26	Pharmacophore modeling using APEX-3D software (MSI) [527]		(S)-Glu, (S)-Asp, (S)-AP4, (S)-SOP, (2S)-4CH2Glu, (S)-Gla, (2S)-CCG-I, (2SR,3RS)-CPrAP4, (2SR,3SR)-CPrAP4, (1S,3S)-ACPD, (2SR,4SR)-CpeAP4, (2SR,4RS)-CpeAP4, ACPT-I, (+)-ACPT-III						Pharmacophore model including key features for ligand activity: (i) the presence of two hydrogen bond donor groups; (ii) the presence of three hydrogen bond acceptor groups. Additional regions are predicted to interact with mGluR4, including the oxygen atom of phosphonic and phosphoric groups of (S)-Glu analogues, the carboxylic groups of (S)-Glu, ACPT-I, and (+)-ACPT-III, and the presence of cycloalkyl rings of CPrAP4, CpeAP4, ACPT-I, and (+)-ACPT-III [527].
Metabotropic Glutamate Receptor 5 (MGluR5) Antagonists / Negative Allosteric Modulators (NAMs)
Entry	Method(s)	Ligand(s)								Results/Conclusions
27	Pharmacophore modeling using Accelrys Discovery Studio 4.0 (DS) software [528]	Pyridyl and phenyl substituted oxadiazoles, 5-aryl-3-acylpyridinyl-pyrazoles, 1-aryl-4-acylpyridinyl-imidazoles, aryl azetidinyl oxadiazoles, N-aryl pyrrolidinonyl oxadiazoles								Pharmacophore model including common key features: (i) one hydrogen bond acceptor feature; (ii) one hydrophobic feature; (iii) two hydrophobic aromatic features; (iv) two excluded volumes [465].
5-Hydroxytryptamine Receptor 1A (5-HT1AR) Agonists
Entry	Method(s)	Ligand(s)								Results/Conclusions
28	QSAR using 2D molecular descriptors by MOE v. 2004.0314 programs [529]	2-[ω-(4-Arylpiperazin-1-yl)alkyl]perhydropyrrolo-[1,2-c]imidazoles, 2-[ω-(4-arylpiperazin-1-yl)alkyl]perhydroimidazo[1,5-a]pyridines								Steric parameters contribute most significantly to the 5-HT1AR agonist activity. The number of rotatable bonds, partial charge descriptors, subdivided surface area descriptors, and an indicator variable for carbonyl oxygens also influence the 5-HT1AR agonist activity of the ligands [530].
29	CoMFA using SYBYL 5.5 program [434]	Arylpiperazines, (aryloxy)propanolamines, tetrahydropyridyl indoles								Arylpiperazines: the introduction of steric groups is favorable close to the aromatic ring and unfavorable near the basic nitrogen atom. The presence of electronegative substituents near the ortho position of the aromatic ring is beneficial for activity. (Aryloxy)propanolamines: the introduction of bulky and electronegative substituents close to the ortho and meta positions of the aromatic ring is beneficial for the activity. The presence of bulky and electropositive groups near the para position of the aromatic ring is favorable as well as the introduction of electropositive substituents near the basic nitrogen atom. Tetrahydropyridylindoles: the steric parameters contribute most significantly to the activity. The introduction of bulky and hydrogen bond donor groups at 5-position of índole ring is predicted to be beneficial for the activity [531].
30	CoMFA using SYBYL 5.5 program [434]	3-(1,2,5,6-Tetrahydropyridin-4-yl)índole derivatives								The steric parameters contribute most significantly to the 5-HT1AR agonist activity. The presence of bulky substituents in the plane of índole 5-position is beneficial for 5-HT1AR activity, whereas bulky substituents located out of a plane is expected to decrease the activity. There is also a preference for coplanarity between indole and tetrahydropyridine rings. Using as a reference a 5-CONH2 analog, the presence of oxygen and hydrogen atoms of carboxamide moiety contributes positively to 5-HT1AR activity [532].
31	CoMFA using SYBYL 6.0 program [434]	Bicyclohydantoin-phenylpiperazines								The electrostatic parameters contribute most significantly to the 5-HT1AR agonist activity. The key features for agonist activity are: (i) the introduction of bulky substituents at ortho and meta positions of the phenyl ring; (ii) the introduction of electron-withdrawing substituents at ortho and meta positions of the phenyl ring. The presence of bulky and electron-withdrawing substituents is expected to have a negative effect on activity [533].
32	Pharmacophore modeling and CoMFA using DISCO [534] and SYBYL programs [434]	Pyridazinothiazepines, pyridazinooxazepines								Pharmacophore model including common key features for ligand activity: (i) two hydrophobic ring features (phenyl and 3(2H)-pyridazinone rings); (ii) four hydrogen bond donor features (N atom of protonated amine, N1 atom and the two lone pairs of O atom of carbonyl group of 3(2H)-pyridazinone ring); (iii) two hydrogen bond acceptor features (O atom of carbonyl group and N1 atom of 3(2H)-pyridazinone ring; (iv) O atom of carbonyl group interacting to the N atom of oxazepine or thiazepine rings), using as reference the ligand GYKI16527 [535].
33	Pharmacophore modeling and CoMFA using GALAHAD program [536-538]	Arylpiperazines								Pharmacophore model including common key features for ligand activity: (i) one hydrogen bond acceptor feature; (ii) one positively charged group; (iii) one aromatic ring feature; (iv) one hydrophobic feature. The steric parameters contribute most significantly to the 5-HT1AR agonist activity. The introduction of bulky substituents, as benzothiophene, and electropositive substituents attached to benzothiophene ring may enhance activity. Moreover, the presence of electronegative substituents surrounding the dihydrobenzodioxepin ring may have a positive effect on activity [539].
5-Hydroxytryptamine Receptor 1A (5-HT1AR) Agonists
Entry	Method(s)	Ligand(s)					Results/Conclusions
34	Pharmacophore modeling using CATALYST 4.6 program [517]	(2-Alkoxy)phenylpiperazine derivatives of 1-(2-hydroxy-3-(4-arylpiperazin-1-yl)propyl)-5,5-diphenylimidazolidine-2,4-dione with alkyl or ester substituents at N3 of the hydantoin ring					Pharmacophore model including common key features for ligand activity: (i) one hydrogen bond acceptor; (ii) one positively charged group; (iii) one aromatic ring feature; (iv) one hydrophobic feature. The inter-feature distance range between hydrogen bond acceptor and hydrophobic features is [5.53-5.62 Å], between hydrogen bond acceptor and positively charged group is [5.13-6.00 Å], between hydrogen bond acceptor and aromatic ring is [10.08-11.68 Å], between hydrophobic feature and positively charged group is [7.60-8.08 Å], between hydrophobic and aromatic ring features is [12.24-13.91 Å], and between positively charged group and aromatic ring feature is [5.68-5.69 Å] [540, 541].
35	Pharmacophore modeling using Accelrys Discovery Studio versions 3.5 (DS) software [542]	(R)-8-OH-DPAT, quetiapine, olanzapine, ziprasidone, 5-methyl urapidil, BMY14802, JB788, S14671, F15599, F13714, 1,3-dioxolane derivatives, pyridyl-fused 3-amino chroman derivatives, 1-(meta-trifluoromethylphenyl) piperazines					Pharmacophore modeling including common key features for ligand activity: (i) one positively ionizable group; (ii) one hydrogen bond acceptor feature; (iii) three hydrophobic features; (iv) seven excluded volumes [543].
36	Pharmacophore modeling using GRID 22 program [544]	8-OH-DPAT, buspirone, vilazodone, aripiprazole, F-13640					Pharmacophore modeling including common key features for ligand activity: (i) two hydrophobic features surrounded by TM5/TM6 and by TM2/TM7/ECL2; (ii) one positive ionizable feature interacting with Asp; (iii) one hydrogen bond acceptor feature interacting with Tyr; (iv) three excluded volumes [162].
5-Hydroxytryptamine Receptor 2A (5-HT2AR) Antagonists
Entry	Method(s)	Ligand(s)					Results/Conclusions
37	QSAR performed by GRID 22 [544] and GOLPE 4.6.0 programs [545] and using GRID/GOLPE descriptors	Butyrophenones					The interaction of hydrophobic groups in two areas, one at the bottom of the pocket near Leu163 and the other in the center near the side chains of Val and Phe residues, is expected to increase the binding affinity. The interaction of these ligands near the oxygen atom of Asp residue, the indolic nitrogen of Trp residue, at the bottom near the Ser residue, the side chain of Asn residue, and close to other Ser and Trp residues are favorable for antagonistic activity [546].
38	QSAR performed by MDL QSAR software package, version 2.2 (Symyx) using electronic and molecular parameters [547]	1-Benzhydryl-piperazines and 1-arylpiperazines with xanthine moiety at N4					The binding affinity of these ligands to 5-HT2AR correlates positively with the lipophilicity of ligands, the largest negative charge associated to O6 atom of xanthine moiety, and with the partial atomic charge of N4 atom of piperazine moiety [547].
39	QSAR by DRAGON software (version 1.11-2001) [514] and using DRAGON descriptors	2-Alkyl-4-aryl-pyrimidine fused heterocycles					A lower number of rotatable bonds, a more hydrophobic nature of the ligands, and lower polar surface area are expected to be favorable for binding affinity [548].
40	CoMFA using SYBYL 5.5 program [434]	3-(1,2,5,6-Tetrahydropyridine-4-yl)índole derivatives					The introduction of bulky substituents around the 5-position of indole ring is unfavorable for activity, whereas the presence of bulky groups at the N1 position of pyridine ring and at the N1 position of the indole ring is expected to be beneficial for activity. The introduction of electronegative substituents around the 5-position of the indole ring and of electropositive substituents above 5- and 6-carbons of the indole ring may increase the activity [532].
41	CoMFA using SYBYL 7.0 program [434]	Hexahydro- and octahydropyrido[1,2-c]pyrimidine derivatives					The introduction of bulky substituents in the proximity to the para position in the benzene ring attached to the piperazine ring and the absence of substituents at ortho position may enhance activity. The presence of bulky groups placed in the proximity of piperazine ring and at the C4 position of the imide moiety is also beneficial for activity. The introduction of electronegative substituents in imide and piperazine moieties may increase the affinity [549].
5-Hydroxytryptamine Receptor 2A (5-HT2AR) Antagonists
Entry	Method(s)	Ligand(s)						Results/Conclusions
42	CoMSIA using SYBYL 7.2 program [434]	Tetrahydrofuran derivatives, benzamides, 3-aminoethyl-1-tetralones, piperazines, benzothiazepines, pyrrolobenzodiazepines, clozapine, flupentixol, haloperidol, loxapine, mesoridazine, olanzapine, quetiapine, risperidone, sertindole, thiothixene, thioridazine, compazine, ziprasidone						The electrostatic, hydrophobic, and hydrogen bond donor parameters contribute most significantly to the binding affinity towards 5-HT2A, comparing to steric and hydrogen bond acceptor parameters [550].
43	Pharmacophore modeling using MOE v. 2007.09 program [551]	Ketanserin, risperidone, ritanserin, spiperone, clozapine, sertindole, setoperone, chlorpromazine, cyproheptadine, tefludazine, 5H-thiazolo[3,2-a]pyrimidine-5-one derivatives						Pharmacophore model including common key features for 5-HT2A antagonist activity: (i) two hydrogen bond acceptor features; (ii) one aromatic ring or hydrophobic feature with two parallel features for π orbital accommodation; (iii) one aromatic ring feature with one hydrogen bond donor group; (iv) one hydrophobic feature [552].
44	Pharmacophore modeling using MOE v. 2008.10 program [553]	Thiophene derivatives						Pharmacophore model including the common key features for ligand activity: (i) one aromatic ring feature; (ii) one positively ionizable group containing a nitrogen atom; (iii) one hydrogen bond acceptor feature; (iv) one hydrophobic or aromatic feature attached to the positively ionizable group. The inter-feature distance range between the positively ionizable group and the hydrogen acceptor group is [6.6-10.3 Å], between aromatic ring feature and the hydrogen bond acceptor feature is [3.1-3.8 Å], between aromatic ring feature and the positively ionizable group is [7.4-8.8 Å], and the angle between the positively ionizable group and the plane of aromatic ring feature is [141.0-152.9 Å]o [554].
45	Pharmacophore modeling using MOE v. 2008.10 programs [553]	4-Nitroindole derivatives						Pharmacophore model including the common key features for ligand activity: (i) two aromatic ring features; (ii) one positively ionizable group; (iii) one hydrophobic feature [555].
46	Pharmacophore modeling using GRID 22 software [544]	Ketanserin						Pharmacophore model including the key features for ligand activity: (i) one positively ionizable amino group; (ii) two hydrophobic features; (iii) one hydrophobic feature [480].
5-Hydroxytryptamine receptor 2C (5-HT2CR) antagonists
Entry	Method(s)	Ligand(s)						Results/Conclusions
47	QSAR by DRAGON software (v.1.11-2001) [514] and using Dragon descriptors	Isoindoline						The binding affinity of these ligands are correlated to several atomic descriptors, in particular, the eigenvalue n.2 and the eigenvalue n.5 of the Burden matrix, atomic van der Waals volume to path length 2 and 8 of the Moran autocorrelations and path length 2 of Geary autocorrelation, polarizability to the highest eigenvalue n.1 and n.6 of the Burden matrix, and Sanderson electronegativity to path length 4 of Geary autocorrelation descriptors [556].
48	QSAR by D-CENT QSAR program [557, 558] using quantum chemical parameters	N-Benzylphenethylamines						The binding affinity was correlated negatively with total atomic electrophilic superdelocalizability of atom 3 and atom 13, the orbital electrophilic superdelocalizability of the highest occupied molecular orbital localized on atom 20, and the local atomic electronic chemical potential of atom 22. On the other hand, the binding affinity was correlated positively with Fukui index of the second highest occupied molecular orbital localized on atom 15 and Fukui index of the lowest vacant molecular orbital localized on atom 17 [559].
49	CoMFA using SYBYL 7.0 program [434]	Library of 24 structurally diverse 5-HT2CR antagonists						The introduction of bulky substituents in the regions where methyl and propyl groups are located may enhance activity, whereas the presence of bulky groups in the proximity of índole group is expected to decrease activity. The presence of electronegative substituents near the amide moiety and positively charged groups is favorable for antagonistic activity [488].
50	Pharmacophore modeling using Accelrys Discovery Studio version 2.1 (DS) software [560]	Library of 24 structurally diverse 5-HT2CR antagonists						Pharmacophore model including the common key features for ligand activity: (i) three hydrophobic features; (ii) one positively ionizable group; (iii) one hydrogen acceptor feature [488].
51	Pharmacophore modeling using CATALYST 4.6 program [517]	Diaryl substituted pyrrolidinones and pyrrolones						Pharmacophore model including the common key features for ligand activity: (i) one positively ionizable group; (ii) one hydrogen bond acceptor feature; (iii) one aromatic ring feature; (iv) three hydrophobic features [561].