Tarun Jha

QSAR Study on the Affinity of Some Arylpiperazines towards the 5-HT1A/α1-Adrenergic Receptor Using the E-State Index

QSAR models represent the relationship of biological activity with either physicochemical parameters or structural indices. QSAR study was performed on some arylpiperazines as 5-HT(1A)/alpha(1)-adrenergic receptor antagonists using E-state indices to identify the pharmacophoric requirements. It was found that some of the atoms played important roles to both activities and some played important role in selectivity of compound to the 5-HT(1A) antagonistic activity. The presence of COONHPr group at the ortho-position of the phenyl ring might be disadvantageous and Br at meta-position might be conducive to the activity. COOPr at the ortho-position might be disfavored the adrenergic alpha(1)-antagonistic activity, thus increase the selectivity.

Exploring pyrazolo[3,4-d]pyrimidine phosphodiesterase 1 (PDE1) inhibitors: a predictive approach combining comparative validated multiple molecular modelling techniques

Phosphodiesterase 1 (PDE1) is a potential target for a number of neurodegenerative disorders such as Schizophrenia, Parkinson’s and Alzheimer’s diseases. A number of pyrazolo[3,4-d]pyrimidine PDE1 inhibitors were subjected to different molecular modelling techniques [such as regression-based quantitative structure-activity relationship (QSAR): multiple linear regression, support vector machine and artificial neural network; classification-based QSAR: Bayesian modelling and Recursive partitioning; Monte Carlo based QSAR; Open3DQSAR; pharmacophore mapping and molecular docking analyses] to get a detailed knowledge about the physicochemical and structural requirements for higher inhibitory activity. The planarity of the pyrimidinone ring plays an important role for PDE1 inhibition. The N-methylated function at the 5th position of the pyrazolo[3,4-d]pyrimidine core is required for interacting with the PDE1 enzyme. The cyclopentyl ring fused with the parent scaffold is necessary for PDE1 binding potency. The phenylamino substitution at 3rd position is crucial for PDE1 inhibition. The N2-substitution at the pyrazole moiety is important for PDE1 inhibition compared to the N1-substituted analogues. Moreover, the p-substituted benzyl side chain at N2-position helps to enhance the PDE1 inhibitory profile. Depending on these observations, some new molecules are predicted that may possess better PDE1 inhibition.

First molecular modeling report on novel arylpyrimidine kynurenine monooxygenase inhibitors through multi-QSAR analysis against Huntington’s disease: A proposal to chemists!

Huntingtons disease (HD) is caused by mutation of huntingtin protein (mHtt) leading to neuronal cell death. The mHtt induced toxicity can be rescued by inhibiting the kynurenine monooxygenase (KMO) enzyme. Therefore, KMO is a promising drug target to address the neurodegenerative disorders such as Huntingtons diseases. Fiftysix arylpyrimidine KMO inhibitors are structurally explored through regression and classification based multi-QSAR modeling, pharmacophore mapping and molecular docking approaches. Moreover, ten new compounds are proposed and validated through the modeling that may be effective in accelerating Huntingtons disease drug discovery efforts.

Design of dual MMP-2/HDAC-8 inhibitors by pharmacophore mapping, molecular docking, synthesis and biological activity

Recent analyses have highlighted the promotion of cancer migration and invasion, mediated through HDAC via MMP-2 and MMP-9. Since both class 1 HDACs and MMP-2/9 are involved in the migration and invasion of cancer, an attempt has been taken to design dual MMP-2/HDAC-8 inhibitors by pharmacophore mapping and molecular docking approaches. The designed molecules were synthesized and showed a range of inhibitory activity against different MMP subtypes. Most of these designed compounds were selective towards MMP-2 but less potent against anti-targets like MMP-8, -12, etc. The highly active MMP-2 inhibitors were also found to be active towards HDAC-8 but less potent against other class 1 HDACs (HDAC-1 and -2). Molecular dynamics simulations revealed that the designed compounds may be acting through a distinct mechanism of action in the ‘acetate ion channel’ of HDAC-8. Some potent dual MMP-2/HDAC-8 inhibitors were further explored for in vitro cellular assays against human lung carcinoma cell line A549. These analyses revealed that some of these dual inhibitors have considerable anti-migratory and anti-invasive properties. The work may help to obtain some useful dual inhibitors.

Comparative validated molecular modeling of p53-HDM2 inhibitors as antiproliferative agents.

Tumor suppressor protein p53 regulates the cell cycle and inhibits tumor growth. It is inactivated by mutation or binding with human double minute 2 (HDM2) protein. The HDM2 is a promising target for treatment of p53 protein related cancers. Molecular modeling techniques such as 2D-QSAR, pharmacophore mapping and 3D-QSAR analyses were performed on 155 structurally diverse HDM2 inhibitors to understand structural and physicochemical requirements for higher activity. The linear and spline 2D-QSAR models were developed through multiple linear regression and genetic functional algorithm methods. The 2D-QSAR models suggested that number of fluorine, chlorine, tertiary nitrogen atoms as well as donor feature, stereogenic centers and higher value of solvent accessible surface area are important features in defining activity. Monte Carlo method was applied to generate QSAR models that determined structural indicators (alerts) for increase or decrease of the biological activity. Ligand-based pharmacophore mapping showed importance of two hydrophobic, one hydrophobic aromatic, one ring aromatic and one donor features. The structure-based pharmacophore model demonstrated significance of two hydrophobic, one ring aromatic and two acceptor features. The pharmacophore (ligand) aligned structures were subjected to 3D-QSAR analyses. The structure-based pharmacophore was also used for pharmacophore restraint molecular docking to analyze ligand-receptor interactions and for adjudging predictability as well as validation of different modeling techniques. These comparative molecular modeling techniques may help to design novel HDM2 inhibitors.

Comparative QSAR modelling of 2-phenylindole-3-carbaldehyde derivatives as potential antimitotic agents

QSAR modelling was done on some 2-phenylindole-3-carbaldehyde derivatives to find out structural requirements for more active antimitotic agents. Four statistical methods were used to develop models. The results show the importance of ETSA indices, RTSA indices, IC1, SIC4, Jhetv and MSD on the activity. Electrostatic potential charges of atoms, increased surface area, and presence of bulky group along Y-axis and chlorine substitution were also found to be important.

Combating breast cancer with non-steroidal aromatase inhibitors (NSAIs): Understanding the chemico-biological interactions through comparative SAR/QSAR study

It is a challenging task to design target-specific and less toxic non-steroidal aromatase inhibitors (NSAIs) though the modeling studies for designing anti-aromatase molecules have been continuing for more than two decades to fight the dreaded estrogen-dependent breast cancer. In this article, different validated QSAR models are developed and analyzed to understand important physicochemical and structural parameters modulating the aromatase inhibitory activity of NSAIs. Physicochemical properties such as molar refractivity and dipole moment are found to be the most important parameters for controlling aromatase inhibition. This indicates the characteristic of bulky, complex and steric properties as well as, the flexibility of molecules is playing pivotal roles for aromatase inhibition. In many cases, hydrophobicity also plays important contribution. Regarding the structural point of view, some important indicator parameters are also found to be important for aromatase inhibitory activity. Though azole function is playing a crucial role by coordinating the heme moiety of the aromatase enzyme, the imidazole or the imidazolylmethyl ring systems may be better NSAIs than triazole, tetrazole or other azoles. The 4-pyridylmethyl group containing compounds are also found to be better NSAIs. The QSAR study, in a nutshell, provides a detailed understanding of the effectivity of NSAIs which is dependent mainly on the shape and size as well as the steric features of molecules and the heme-coordinator azole functions. These findings may open up a new horizon for designing new potential NSAIs that can be effective to reduce the mortality rate of breast cancer in future.

Validated predictive QSAR modeling of N-aryl-oxazolidinone-5-carboxamides for anti-HIV protease activity

Validated predictive QSAR modeling was done on some N-aryl-oxazolidinone-5-carboxamides for higher anti-HIV protease activities. Stepwise regression developed significant models showing importance of atom based descriptors like RTSA indices, Wang-Ford charges and different whole molecular descriptors. The true predictabilities of QSAR models were justified by challenging these against an external dataset. A representative high active compound was predicted by this modeling. It showed that internal and external validations may lead to the same conclusion.

Exploring structural requirements of 1-N-substituted thiocarbamoyl-3-phenyl-2-pyrazolines as antiamoebic agents using comparative QSAR modelling

Amoebiasis is a potentially lethal disease and causes 70,000 deaths per year. To find structural requirements for more active antiamoebic agents than metronidazole, comparative QSAR modelling was done on thirty 1-N-substituted thiocarbamoyl-3-phenyl-2-pyrazolines. The best model was obtained by using PLS technique with R(A)(2) and R(CV)(2) value of 88.50% and 82.90%, respectively. Amoebicidal activity may increase when Wang-Ford charges at atom numbers 6 and 12 have large positive values. Number of six-membered ring and sum of Kier-Hall electrotopological states may also increase amoebicidal activity when these have large positive values. Increasing value of rotatable bond fraction, approximate surface area and mean atomic polarizability scaled on carbon atom may be detrimental for antiamoebic activity. Decrease in values of electrostatic potential charges at atom numbers 1 and 12 may be conducive for activity. Electrophilic attacks may be favourable at these positions.

Predictive comparative QSAR modelling of (phenylpiperazinyl-alkyl) oxindoles as selective 5-HT1A antagonists by stepwise regression, PCRA, FA-MLR and PLS techniques

5-Hydroxytryptamine, a neurotransmitter released by 5-HT neurons in raphe nuclei and 5-HT(1A) receptors are involved in the pain mechanism of migraine, prevention of postpartum haemorrhage, CNS effects like sleep, anxiety and thermoregulation. Comparative QSAR study was done on thirtytwo (phenylpiperazinyl-alkyl) oxindoles using stepwise regression, PCRA, FA-MLR and PLS techniques to find structurally significant models. ETSA indices at atom numbers 19, 20 and 22, RTSA indices at atom numbers 6, 10 and 20, charge at atom number 19 and presence of chlorine at the atom number 6 may be conducive for the receptor inhibition. Electrophilic attack at atom number 21 may be unfavourable but nucleophilic attack at atom numbers 8 and 14 may be beneficial for % 5-HT(1A) inhibition.