title: Molecular Recognition of Azelaic Acid and Related Molecules with DNA Polymerase I Investigated by Molecular Modeling Calculations.
abstract: Molecular recognition has central role on the development of rational drug design. Binding affinity and interactions are two key components which aid to understand the molecular recognition in drug-receptor complex and crucial for structure-based drug design in medicinal chemistry. Herein, we report the binding affinity and the nonbonding interactions of azelaic acid and related compounds with the receptor DNA polymerase I (2KFN). Quantum mechanical calculation was employed to optimize the modified drugs using B3LYP/6-31G(d,p) level of theory. Charge distribution, dipole moment and thermodynamic properties such as electronic energy, enthalpy and free energy of these optimized drugs are also explored to evaluate how modifications impact the drug properties. Molecular docking calculation was performed to evaluate the binding affinity and nonbonding interactions between designed molecules and the receptor protein. We notice that all modified drugs are thermodynamically more stable and some of them are more chemically reactive than the unmodified drug. Promise in enhancing hydrogen bonds is found in case of fluorine-directed modifications as well as in the addition of trifluoroacetyl group. Fluorine participates in forming fluorine bonds and also stimulates alkyl, pi-alkyl interactions in some drugs. Designed drugs revealed increased binding affinity toward 2KFN. A1, A2 and A3 showed binding affinities of -8.7, -8.6 and -7.9 kcal/mol, respectively against 2KFN compared to the binding affinity -6.7 kcal/mol of the parent drug. Significant interactions observed between the drugs and Thr358 and Asp355 residues of 2KFN. Moreover, designed drugs demonstrated improved pharmacokinetic properties. This study disclosed that 9-octadecenoic acid and drugs containing trifluoroacetyl and trifluoromethyl groups are the best 2KFN inhibitors. Overall, these results can be useful for the design of new potential candidates against DNA polymerase I.
authors.affiliation: Division of Computer-Aided Drug Design, BICCB, Green Research Centre, 38 Green Road West, Dhaka, 1205, Bangladesh.|Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, 1000, Bangladesh.
authors.forename: Jakaria
authors.initials: J
authors.lastname: Shawon
authors.affiliation: Division of Computer-Aided Drug Design, BICCB, Green Research Centre, 38 Green Road West, Dhaka, 1205, Bangladesh.|Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, 1000, Bangladesh.
authors.forename: Akib Mahmud
authors.initials: AM
authors.lastname: Khan
authors.affiliation: Division of Computer-Aided Drug Design, BICCB, Green Research Centre, 38 Green Road West, Dhaka, 1205, Bangladesh.
authors.forename: Adhip
authors.initials: A
authors.lastname: Rahman
authors.affiliation: Division of Computer-Aided Drug Design, BICCB, Green Research Centre, 38 Green Road West, Dhaka, 1205, Bangladesh.
authors.forename: Mohammad Mazharol
authors.initials: MM
authors.lastname: Hoque
authors.affiliation: Department of General Studies, Jubail University College, Jubail Industrial City, 31961, Saudi Arabia.
authors.forename: Mohammad Abdul Kader
authors.initials: MAK
authors.lastname: Khan
authors.affiliation: Fakultät für Chemie und Biochemie, Organische Chemie I, Ruhr-Universität Bochum, Universitätsstrasse 150, 44801, Bochum, Germany.
authors.forename: Mohammed G
authors.initials: MG
authors.lastname: Sarwar
authors.affiliation: Division of Computer-Aided Drug Design, BICCB, Green Research Centre, 38 Green Road West, Dhaka, 1205, Bangladesh. mahalim@grc-bd.org.|Institut Lumière Matière, Université Lyon 1 - CNRS, Université de Lyon, 69622, Villeurbanne Cedex, France. mahalim@grc-bd.org.
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Halim
mesh_terms: D001665:Binding Sites; D004256:DNA Polymerase I / Q000737:chemistry*; D003998:Dicarboxylic Acids / Q000737:chemistry* / Q000493:pharmacokinetics; D004583:Electrons; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D062105:Molecular Docking Simulation; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D003998:Dicarboxylic Acids; D004256:DNA Polymerase I; C010038:azelaic acid
keywords: Acne; Azelaic acid; DNA polymerase I; Density functional theory; Molecular docking; Nonbonding interactions; Rational drug design