Hydrogen Bond Acceptor Groups Research Articles

Comparative molecular similarity indices analysis of some 1-substituted imidazole analogs as Candida albicans P450-demethylase inhibitors

A three-dimensional quantitative structure–activity relationship of 66 structurally and functionally diverse series of 1-substituted imidazoles with antifungal activity was studied using the CoMSIA method. The compounds were divided into a training set of 56 molecules and a test set of 10 molecules. The optimum CoMSIA model obtained for the training set were all statistically significant with cross-validated coefficients (q 2) of 0.725 and conventional coefficients (r ncv 2 ) of 0.998. The predictive ability of CoMSIA was determined using a test set of ten imidazole derivatives. CoMSIA model (Model 1) obtained from steric, electrostatic, and H-bond acceptor fields were found to have best predictivity with a predictive correlation coefficient (r pred 2 ) of 0.60. Based upon the information derived from CoMSIA, it is evident that steric, electrostatic, and hydrogen bond acceptor groups may be important for the design of more potent imidazole analogs as potent Candida P450DM inhibitors.

Discovery of 3-(5-Chloro-2-furoyl)-3,7-diazabicyclo[3.3.0]octane (TC-6683, AZD1446), a Novel Highly Selective α4β2 Nicotinic Acetylcholine Receptor Agonist for the Treatment of Cognitive Disorders

Diversification of essential nicotinic cholinergic pharmacophoric elements, i.e., cationic center and hydrogen bond acceptor, resulted in the discovery of novel potent α4β2 nAChR selective agonists comprising a series of N-acyldiazabicycles. Core characteristics of the series are an exocyclic carbonyl moiety as a hydrogen bond acceptor and endocyclic secondary amino group. These features are positioned at optimal distance and with optimal relative spatial orientation to provide near optimal interactions with the receptor. A novel potent and highly selective α4β2 nAChR agonist 3-(5-chloro-2-furoyl)-3,7-diazabicyclo[3.3.0]octane (56, TC-6683, AZD1446) with favorable pharmaceutical properties and in vivo efficacy in animal models has been identified as a potential treatment for cognitive deficits associated with psychiatric or neurological conditions and is currently being progressed to phase 2 clinical trials as a treatment for Alzheimer's disease.

Polymorphism, Hydrogen Bond Properties, and Vibrational Structure of 1H-Pyrrolo[3,2-h]Quinoline Dimers

Two forms of cyclic, doubly hydrogen-bonded dimers are discovered for crystalline 1H-pyrrolo[3,2-h]quinoline, a bifunctional molecule possessing both hydrogen bond donor and acceptor groups. One of the forms is planar, the other is twisted. Analysis of IR and Raman spectra, combined with DFT calculations, allows one to assign the observed vibrations and to single out vibrational transitions which can serve as markers of hydrogen bond formation and dimer structure. Raman spectra measured for samples submitted to high pressure indicate a transition from the planar towards the twisted structure. Formation of intermolecular hydrogen bonds leads to a large increase of the Raman intensity of the NH stretching band: it can be readily observed for the dimer, but is absent in the monomer spectrum.

New hypotheses for the binding mode of 4- and 7-substituted indazoles in the active site of neuronal nitric oxide synthase

Taking into account the potency of 4- and 7-nitro and haloindazoles as nNOS inhibitors previously reported in the literature by our team, a multidisciplinary study, described in this article, has recently been carried out to elucidate their binding mode in the enzyme active site. Firstly, nitrogenous fastening points on the indazole building block have been investigated referring to molecular modeling hypotheses and thanks to the in vitro biological evaluation of N1- and N2-methyl and ethyl-4-substituted indazoles on nNOS. Secondly, we attempted to confirm the importance of the substitution in position 4 or 7 by a hydrogen bond acceptor group thanks to the synthesis and the in vitro biological evaluation of a new analogous 4-substituted derivative, the 4-cyanoindazole. Finally, by opposition to previous hypotheses describing NH function in position 1 of the indazole as a key fastening point, the present work speaks in favour of a crucial role of nitrogen in position 2.

Binding Modes and Pharmacophore Modelling of Thermolysin Inhibitors

In the present paper 25 known thermolysin inhibitors were docked into thermolysin using the Internal Coordinate Mechanics (ICM) software. Pharmacophore models based on thermolysin binding modes and activity profiles were generated using the LigandScout program. The docking studies indicated that all 25 inhibitors coordinated the catalytic zinc in bidentate or monodentate geometry. A 'three-point' pharmacophore model was proposed which consisted of a hydrophobic group, a negative ionizable group and a hydrogen bond acceptor group. Finally the pharmacophore model has been tested against a small compound library containing 18 highly, moderately, less active as well as inactive compounds. The screening indicated that the pharmacophore model could, identify highly active compounds in front of inactive or less active ones.

The solvates of sulfamerazine: structural, thermochemical, and desolvation studies

The ability of an antibacterial agent, sulfamerazine (SMZ), to form solvates is investigated. Six solvates, with the solvents 1,4-dioxane (1:1 and 1:0.5), dimethylacetamide, dimethylformamide, cyclopentanone and 3-picoline, were identified and characterized by various analytical techniques, namely, differential scanning calorimetry, thermogravimetric analysis, and X-ray diffraction. Crystal structure analysis revealed a dimer via a pair of intermolecular N–H⋯N hydrogen bonds between two molecules of SMZ and extended hydrogen bonded networks mediated by the solvent molecules. The conformationally flexible SMZ molecule adopts different conformations in the crystal structures. Thermal analysis established the stability and confirmed molar ratios of the reported solvates. Crystal structures of the sulfonamide drugs were retrieved from the Cambridge Structural Database (CSD) and analyzed to rationalize the factors that favour the solvate formation in sulfonamide drugs. It was found that the CSD statistics under-represent the true prevalence of solvates and polymorphs of sulfonamide drugs, and solvents that contain hydrogen bond acceptor groups have higher likelihood of forming solvates with sulfonamide drugs. Furthermore, a one-dimensional hydrogen bond chain motif was predominantly observed in the crystal structures of solvates/hydrates.

Interaction of Arylpiperazines with the Dopamine Receptor D2 Binding Site

The docking of several 1-benzyl-4-arylpiperazines to the dopamine receptor (DAR) D2 was examined. The results demonstrated that the interaction of protonated N1 of the piperazine ring with Asp 86 (III.32) and edge-to-face interactions of the aromatic ring of the arylpiperazine part of the ligand with Phe 178 (VI.44), Trp 182 (VI.48) and Tyr 216 (VII.58) of the receptor, represent the major stabilizing forces. Besides, the hydrogen bond acceptor group in position 2 of the phenylpiperazine aromatic ring could build one more hydrogen bond with Trp 182 (VI.48). Bulky substituents in position 4 were not tolerated due to the unfavorable sterical interaction with Phe 178 (VI.44). Substituents in position 2 and 3 were found to be sterically well tolerated. Introduction of electron attractive -NO2 group in position 3 of aryipiperazines decreased, while electron donors (-OMe) and the second aromatic ring (naphthyl) increased the binding affinity comparing to that of the phenylpiperazine 1. This can be explained in terms of favoured edge-to-face interactions in ligands with a high negative electrostatic surface potential (ESP) in the centre of aromatic residue of arylpiperazines. Thus, besides the salt bridges and hydrogen bonds, edge-to-face interactions significantly contribute to arylpiperazine ligands to form complexes with the DAR D2. Phe 178 (VI.44), Trp 182 (VI.48) and Tyr 216 (VII.58) can be considered as a part of the ancillary DAR D2 pocket preserved in most G protein-coupled receptors of the A class and obviously, the arylpiperazine structural motif represents one of the privileged structures that bind to this pocket.

Docking studies of benzylidene anabaseine interactions with α7 nicotinic acetylcholine receptor (nAChR) and acetylcholine binding proteins (AChBPs): Application to the design of related α7 selective ligands

AChBPs isolated from Lymnaea stagnalis (Ls), Aplysia californica (Ac) and Bulinus truncatus (Bt) have been extensively used as structural prototypes to understand the molecular mechanisms that underlie ligand-interactions with nAChRs [1]. Here, we describe docking studies on interactions of benzylidene anabaseine analogs with AChBPs and α7 nAChR. Results reveal that docking of these compounds using Glide software accurately reproduces experimentally-observed binding modes of DMXBA and of its active metabolite, in the binding pocket of Ac. In addition to the well-known nicotinic pharmacophore (positive charge, hydrogen-bond acceptor, and hydrophobic aromatic groups), a hydrogen-bond donor feature contributes to binding of these compounds to Ac, Bt, and the α7 nAChR. This is consistent with benzylidene anabaseine analogs with OH and NH2 functional groups showing the highest binding affinity of these congeners, and the position of the ligand shown in previous X-ray crystallographic studies of ligand-Ac complexes. In the predicted ligand-Ls complex, by contrast, the ligand OH group acts as hydrogen-bond acceptor. We have applied our structural findings to optimizing the design of novel spirodiazepine and spiroimidazoline quinuclidine series. Binding and functional studies revealed that these hydrogen-bond donor containing compounds exhibit improved affinity and selectivity for the α7 nAChR subtype and demonstrate partial agonism. The gain in affinity is also due to conformational restriction, tighter hydrophobic enclosures, and stronger cation-π interactions. The use of AChBPs structure as a surrogate to predict binding affinity to α7 nAChR has also been investigated. On the whole, we found that molecular docking into Ls binding site generally scores better than when a α7 homology model, Bt or Ac crystal structure is used.

P1-Substituted Symmetry-Based Human Immunodeficiency Virus Protease Inhibitors with Potent Antiviral Activity against Drug-Resistant Viruses

Because there is currently no cure for HIV infection, patients must remain on long-term drug therapy, leading to concerns over potential drug side effects and the emergence of drug resistance. For this reason, new and safe antiretroviral agents with improved potency against drug-resistant strains of HIV are needed. A series of HIV protease inhibitors (PIs) with potent activity against both wild-type (WT) virus and drug-resistant strains of HIV was designed and synthesized. The incorporation of substituents with hydrogen bond donor and acceptor groups at the P1 position of our symmetry-based inhibitor series resulted in significant potency improvements against the resistant mutants. By this approach, several compounds, such as 13, 24, and 29, were identified that demonstrated similar or improved potencies compared to 1 against highly mutated strains of HIV derived from patients who previously failed HIV PI therapy. Overall, compound 13 demonstrated the best balance of potency against drug resistant strains of HIV and oral bioavailability in pharmacokinetic studies. X-ray analysis of an HIV PI with an improved resistance profile bound to WT HIV protease is also reported.

Using Hydrogen-Bonding Interactions To Control the Peptide Secondary Structures and Miscibility Behavior of Poly(l-glutamate)s with Phenolic Resin

We synthesized three low-molecular-weight poly(glutamate)s—poly(γ-methyl l-glutamate) (PMLG), poly(γ-ethyl l-glutamate) (PELG), and poly(γ-benzyl l-glutamate) (PBLG)—through living ring-opening polymerization of their α-amino acid-N-carboxyanhydride derivatives and then blended them with phenolic resin to control the secondary structures of these polypeptides. Each of the three binary blends exhibited a single glass transition temperature (differential scanning calorimetry) and a single-exponential decay of proton spin–lattice relaxation times in the rotating frame [T1ρH; solid state nuclear magnetic resonance (NMR) spectroscopy], characteristic of a miscible system. The strength of the interassociative interactions depended on the nature of the hydrogen bond acceptor groups, increasing in the order phenolic/PELG > phenolic/PMLG > phenolic/PBLG, as evidenced through analyses using Fourier transform infrared (FTIR) spectroscopy and the Painter–Coleman association model. The fractions of α-helical conformat...

Griseofulvin/Carrier Blends: Application of Partial Least Squares (PLS) Regression Analysis for Estimating the Factors Affecting the Dissolution Efficiency

The main aim of the present study was to estimate the carrier characteristics affecting the dissolution efficiency of griseofulvin (Gris) containing blends (BLs) using partial least squares (PLS) regression analysis. These systems were prepared at three different drug/carrier weight ratios (1/5, 1/10, and 1/20) by the solvent evaporation method, a well-established method for preparing solid dispersions (SDs). The carriers used were structurally different including polymers, a polyol, acids, bases and sugars. The BLs were characterised at the solid-state by spectroscopic (Fourier transform infrared spectroscopy), thermoanalytical (differential scanning calorimetry) and X-ray diffraction studies and their dissolution behaviours were quantified in terms of dissolution efficiencies (log DE/DE(Gris)). The correlation between the selected descriptors, including parameters for size, lipophilicity, cohesive energy density, and hydrogen bonding capacity and log DE/DE(Gris) (i.e., DE and DE(Gris) are the dissolution efficiencies of the BLs and the pure drug, respectively) was established by PLS regression analysis. Thus two models characterised by satisfactory coefficient of determination were derived. The generated equations point out that aqueous solubility, density, lipophilic/hydrophilic character, dispersive/polar forces and hydrogen bonding acceptor/donor ability of the carrier are important features for dissolution efficiency enhancement. Finally, it could be concluded that the correlations developed may be used to predict at a semiquantitative level the dissolution behaviour of BLs of other essentially neutral drugs possessing hydrogen bonding acceptor groups only.

Studies of H4R antagonists using 3D-QSAR, molecular docking and molecular dynamics

Three-dimensional quantitative structure-activity relationship studies were performed on a series of 88 histamine receptor 4 (H4R) antagonists in an attempt to elucidate the 3D structural features required for activity. Several in silico modeling approaches, including comparative molecular field analysis (CoMFA), comparative similarity indices analysis (CoMSIA), molecular docking, and molecular dynamics (MD), were carried out. The results show that both the ligand-based CoMFA model (Q (2) = 0.548, R (ncv) (2) = 0.870, R (pre) (2) = 0.879, SEE = 0.410, SEP = 0.386) and the CoMSIA model (Q (2) = 0.526, R (ncv) (2) =0.866, R (pre) (2) = 0.848, SEE = 0.416, SEP = 0.413) are acceptable, as they show good predictive capabilities. Furthermore, a combined analysis incorporating CoMFA, CoMSIA contour maps and MD results shows that (1) compounds with bulky or hydrophobic substituents at positions 4-6 in ring A (R2 substituent), positively charged or hydrogen-bonding (HB) donor groups in the R1 substituent, and hydrophilic or HB acceptor groups in ring C show enhanced biological activities, and (2) the key amino acids in the binding pocket are TRP67, LEU71, ASP94, TYR95, PHE263 and GLN266. To our best knowledge, this work is the first to report the 3D-QSAR modeling of these H4R antagonists. The conclusions of this work may lead to a better understanding of the mechanism of antagonism and aid in the design of new, more potent H4R antagonists.

Molecular modelling study on human histamine H1 receptor and its applications in virtual lead identification for designing novel inverse agonists

Human histamine H1 receptor (HHR1) is one of the G protein-coupled receptors (GPCRs) known for their constitutive activation in the absence of agonist binding. Inverse agonists are the compounds that inhibit this constitutive activity of GPCRs. HHR1 is involved in allergic reactions and is also known to be constitutively active. An updated quantitative pharmacophore model, Hypo1, has been developed using a diverse set of known HHR1 inverse agonists employing the HypoGen algorithm as implemented in Accelrys Discovery Studio 2.1. Hypo1 comprised four pharmacophore features (each one of hydrogen bond acceptor, hydrophobic, ring aromatic and positive ionisable group) along with a high correlation value of 0.944. This pharmacophore model was validated using an external test set containing 25 diverse inverse agonists and CatScramble method. Three chemical databases were screened for novel chemical scaffolds using Hypo1 as a query, to be utilised in drug design. The 3D structure of HHR1 has been constructed using human β2 adrenergic receptor. Molecular docking studies were performed with the database hit compounds using GOLD 4.1 program. The combination of all results led us to identify novel compounds to be deployed in designing new generation HHR1 inverse agonists.

Oxoquinoline Derivatives: Identification and Structure–Activity Relationship (SAR) Analysis of New Anti-HSV-1 Agents

Herpes simplex virus is an important human pathogen responsible for a range of diseases from mild uncomplicated mucocutaneous infections to life-threatening ones. Currently, the emergence of Herpes simplex virus resistant strains increased the need for more effective and less cytotoxic drugs for Herpes treatment. In this work, we synthesized a series of oxoquinoline derivatives and experimentally evaluated the antiviral activity against acyclovir resistant HSV-1 strain as well as their cytotoxity profile. The most active compound (3b), named here as Fluoroxaq-3b, showed a promising profile with a better cytotoxicity profile than acyclovir. The theoretical analysis of the structure-activity relationship of these compounds revealed some stereoelectronic properties such as lower LUMO energy and lipophilicity, besides a higher polar surface area and number of hydrogen bond acceptor groups as important parameters for the antiviral activity. Fluoroxaq-3b showed a good oral theoretical bioavailability, according to Lipinski rule of five, with a promising profile for further in vivo analysis.

Influence of polymer chemistry on crystal growth inhibition of two chemically diverse organic molecules

The purpose of this study was to understand how different polymers affect the crystal growth rates of two chemically diverse organic drug molecules (bifonazole and nimesulide) from the undercooled melt regime close to the glass transition temperature. Bifonazole is an antifungal drug that contains no traditional hydrogen bond donors, only acceptors. In contrast, nimesulide contains both hydrogen bond donor and acceptor groups. Therefore, the potential hydrogen bonding interactions with polymers vary between the two compounds. For bifonazole, poly(vinylpyrrolidone) (PVP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), poly(vinylpyrrolidone-vinyl acetate) (PVP/VA) and poly(acrylic acid) (PAA) were investigated, while for nimesulide, PVP, PVP/VA and poly(vinyl acetate) (PVAc) were probed. Polymers were incorporated at a level of 5%w/w by cryomilling followed by melt quenching. Linear crystal growth rates in the presence and absence of polymers were measured as a function of temperature (18–100 °C for bifonazole and 18–80 °C for nimesulide) using optical microscopy. Differential scanning calorimetry (DSC) and infrared spectroscopy were performed for further characterization. All of the polymers decreased the growth rates of both drugs, however large differences could be observed between polymers in terms of the extent of crystal growth inhibition. For bifonazole, PAA was a notably better crystal growth inhibitor compared to the other polymers. This may be related to formation of specific interactions between the drug and the polymer. For nimesulide, the order of effectiveness was PVP∼PVP/VA>PVAc and, compared to bifonazole, differences seen between polymers were more modest. Infrared (IR) spectroscopy and density functional calculations strongly suggested that amorphous nimesulide formed an intramolecular hydrogen bond. IR spectroscopy showed that drug-polymer intermolecular hydrogen bonding did occur, but was hampered by the partial loss of the hydrogen bond donor to the intramolecular hydrogen bond. Hence the effectiveness of a polymer appears to depend not only on the chemistry of the drug, but also on the availability of hydrogen bonding groups.

Identification and Mechanism of Action of the Acylguanidine MRT-83, a Novel Potent Smoothened Antagonist

There is a clear need to develop novel pharmacological tools to improve our understanding of Smoothened (Smo) function in normal and pathological states. Here, we report the discovery, the mechanism of action, and the in vivo activity of N-(2-methyl-5-(3-(3,4,5-trimethoxybenzoyl)guanidino)phenyl)biphenyl-4-carboxamide (MRT-83), a novel potent antagonist of Smo that belongs to the acylguanidine family of molecules. MRT-83 fits to a proposed pharmacophoric model for Smo antagonists with three hydrogen bond acceptor groups and three hydrophobic regions. MRT-83 blocks Hedgehog (Hh) signaling in various assays with an IC50 in the nanomolar range, showing greater potency than the reference Smo antagonist cyclopamine. MRT-83 inhibits Bodipy-cyclopamine binding to human and mouse Smo but does not modify Wnt signaling in human embryonic kidney 293 transiently transfected with a Tcf/Lef-dependent Firefly luciferase reporter together with a Renilla reniformis luciferase control reporter. MRT-83 abrogates the agonist-induced trafficking of endogenous mouse or human Smo to the primary cilium of C3H10T1/2 or NT2 cells that derive from a pluripotent testicular carcinoma. Stereotaxic injection into the lateral ventricle of adult mice of MRT-83 but not of a structurally related compound inactive at Smo abolished up-regulation of Patched transcription induced by Sonic Hedgehog in the neighboring subventricular zone. These data demonstrate that MRT-83 efficiently antagonizes Hh signaling in vivo. All together, these molecular, functional and biochemical studies provide evidence that MRT-83 interacts with Smo. Thus, this novel Smo antagonist will be useful for manipulating Hh signaling and may help develop new therapies against Hh-pathway related diseases.

Ligand-based in silico 3D-QSAR study of PPAR-γ agonists

The peroxisome proliferator-activated receptor gamma (PPAR-γ) is member of a large family of ligand-activated nuclear transcription factors. The first compounds reported as high-affinity PPAR-γ agonists were a class of antidiabetic agents known as thiazolidinediones or “glitazones”. Quantitative structure activity relationship (QSAR) analyses used to understand the structural factors responsible for PPAR-γ agonistic activity of some thiazolidinedione derivatives. Several pharmacophore-based models indicated the importance of steric, hydrophobic, and hydrogen bond acceptor groups to agonistic activity. The 3D-QSAR analysis was carried out by PHASE program and a statistically reliable model with good predictive power (r2 = 0.9702, q2 = 0.8216) was achieved. The 3D-QSAR plots illustrated insights into the structure activity relationship of these compounds which may helps in the design and development of potent thiazolidinedione derivatives as antidiabetic agents.

X-ray crystallographic structure of an artificial beta-sheet dimer.

This paper describes the X-ray crystallographic structure of a designed cyclic β-sheet peptide that forms a well-defined hydrogen-bonded dimer that mimics β-sheet dimers formed by proteins. The 54-membered ring macrocyclic peptide (1a) contains molecular template and turn units that induce β-sheet structure in a heptapeptide strand that forms the dimerization interface. The X-ray crystallographic structure reveals the structures of the two “Hao” amino acids that help template the β-sheet structure and the two δ-linked ornithine turn units that link the Hao-containing template to the heptapeptide β-strand. The Hao amino acids adopt a conformation that resembles a tripeptide in a β-strand conformation, with one edge of the Hao unit presenting an alternating array of hydrogen-bond donor and acceptor groups in the same pattern as that of a tripeptide β-strand. The δ-linked ornithines adopt a conformation that resembles a hydrogen-bonded β-turn, in which the ornithine takes the place of the i+1 and i+2 residues. The dimers formed by macrocyclic β-sheet 1a resemble the dimers of many proteins, such as defensin HNP-3, the λ-Cro repressor, interleukin 8, and the ribonuclease H domain of HIV-1 reverse transcriptase. The dimers of 1a self-assemble in the solid state into a barrel-shaped trimer of dimers in which the three dimers are arranged in a triangular fashion. Molecular modeling in which one of the three dimers is removed and the remaining two dimers are aligned face-to-face provides a model of the dimers of dimers of closely related macrocyclic β-sheet peptides that were observed in solution.

Virtual Screening-Based Discovery and Mechanistic Characterization of the Acylthiourea MRT-10 Family as Smoothened Antagonists

The seven-transmembrane receptor Smoothened (Smo) is the major component involved in signal transduction of the Hedgehog (Hh) morphogens. Smo inhibitors represent a promising alternative for the treatment of several types of cancers linked to abnormal Hh signaling. Here, on the basis of experimental data, we generated and validated a pharmacophoric model for Smo inhibitors constituted by three hydrogen bond acceptor groups and three hydrophobic regions. We used this model for the virtual screening of a library of commercially available compounds. Visual and structural criteria allowed the selection of 20 top scoring ligands, and an acylthiourea, N-(3-benzamidophenylcarbamothioyl)-3,4,5-trimethoxybenzamide (MRT-10), was identified and characterized as a Smo antagonist. The corresponding acylurea, N-(3-benzamidophenylcarbamoyl)-3,4,5-trimethoxybenzamide (MRT-14), was synthesized and shown to display, in various Hh assays, an inhibitory potency comparable to or greater than that of reference Smo antagonists cyclopamine and N-((3S,5S)-1-(benzo[d][1,3]dioxol-5-ylmethyl)-5-(piperazine-1-carbonyl)pyrrolidin-3-yl)-N-(3-methoxybenzyl)-3,3-dimethylbutanamide (Cur61414). Focused virtual screening of the same library further identified five additional related antagonists. MRT-10 and MRT-14 constitute the first members of novel families of Smo antagonists. The described virtual screening approach is aimed at identifying novel modulators of Smo and of other G-protein coupled receptors.

Docking and 3D-QSAR studies of diverse classes of human aromatase (CYP19) inhibitors

Aromatase (cytochrome 19) inhibitors have emerged as promising candidates for treatment of breast cancer. In search of potent aromatase inhibitors, docking and three-dimensional quantitative structure-activity relationship (3D-QSAR) studies using molecular shape, spatial, electronic, structural and thermodynamic descriptors have been performed on a diverse set of compounds having human aromatase inhibitory activities. An attempt has also been made to include two-dimensional (2D) descriptors in the QSAR studies. The chemometric tools used for model development are genetic function approximation (GFA) and genetic partial least squares (G/PLS). The docking study shows that the important interacting amino acids in the active site cavity are Met374, Arg115, Ile133, Ala306, Thr310, Asp309, Val370 and Ser478. One or more hydrogen bond formation with Met374 is one of the essential requirements for the ligands for optimum aromatase inhibition. The binding is further stabilized by van der Waals interactions with a few non-polar amino acid residues in the active site. The developed QSAR models indicate the importance of different shape, Jurs parameters, structural parameters, topological branching index and E-state index for different fragments. The results obtained from the QSAR analysis are supported by our docking observations. There should be one or two hydrogen bond acceptor groups (like -NO2, -CN) and optimal hydrophobicity for ideal aromatase inhibitors. A GFA model with spline option obtained using 3D descriptors was found to be the best model based on internal validation (Q2=0.668) while the best (externally) predictive model was a GFA model with spline option using combined set (2D and 3D) descriptors (Rpred2=0.687). Based on rm2(overall) criterion, the best model was a G/PLS model (using 3D descriptors) with spline option (rm2(overall)=0.606).