title: Exploring pyrazolo[3,4-d]pyrimidine phosphodiesterase 1 (PDE1) inhibitors: a predictive approach combining comparative validated multiple molecular modelling techniques.
abstract: 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.
authors.affiliation: a Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology , Jadavpur University , P. O. Box 17020, Kolkata 700032 , West Bengal , India.
authors.forename: Sk Abdul
authors.initials: SA
authors.lastname: Amin
authors.affiliation: b Laboratory of Drug Design and Discovery, Department of Pharmaceutical Sciences , Dr. Harisingh Gour University , Sagar 470003 , Madhya Pradesh , India.
authors.forename: Sonam
authors.initials: S
authors.lastname: Bhargava
authors.affiliation: a Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology , Jadavpur University , P. O. Box 17020, Kolkata 700032 , West Bengal , India.
authors.forename: Nilanjan
authors.initials: N
authors.lastname: Adhikari
authors.affiliation: b Laboratory of Drug Design and Discovery, Department of Pharmaceutical Sciences , Dr. Harisingh Gour University , Sagar 470003 , Madhya Pradesh , India.
authors.forename: Shovanlal
authors.initials: S
authors.lastname: Gayen
authors.affiliation: a Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology , Jadavpur University , P. O. Box 17020, Kolkata 700032 , West Bengal , India.
authors.forename: Tarun
authors.initials: T
authors.lastname: Jha
mesh_terms: D001499:Bayes Theorem; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1 / Q000037:antagonists & inhibitors / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011720:Pyrazoles / Q000737:chemistry*; D011743:Pyrimidines / Q000737:chemistry*; D011744:Pyrimidinones / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D011744:Pyrimidinones; C014175:pyrazolo(3,4-d)pyrimidine; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1
keywords: Open3DQSAR; classification-QSAR; machine learning; molecular docking; molecular modelling; pharmacophore mapping; phosphodiesterase 1; pyrazolo[3,4-d]pyrimidine; regression-QSAR