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PARP1 plays a pivotal role in DNA repair within the base excision pathway, making it a promising therapeutic target for cancers involving BRCA mutations. Current study is focused on the discovery of PARP inhibitors with enhanced selectivity for PARP1. Concurrent inhibition of PARP1 with PARP2 and PARP3 affects cellular functions, potentially causing DNA damage accumulation and disrupting immune responses. In step 1, a virtual library of 593 million compounds has been screened using a shape-based screening approach to narrow down the promising scaffolds. In step 2, hierarchical docking approach embedded in Schrödinger suite was employed to select compounds with good dock score, drug-likeness and MMGBSA score. Analysis supplemented with decomposition energy, molecular dynamics (MD) simulations and hydrogen bond frequency analysis, pinpointed that active site residues; H862, G863, R878, M890, Y896 and F897 are crucial for specific binding of ZINC001258189808 and ZINC000092332196 with PARP1 as compared to PARP2 and PARP3. The binding of ZINC000656130962, ZINC000762230673, ZINC001332491123, and ZINC000579446675 also revealed interaction involving two additional active site residues of PARP1, namely N767 and E988. Weaker or no interaction was observed for these residues with PARP2 and PARP3. This approach advances our understanding of PARP-1 specific inhibitors and their mechanisms of action, facilitating the development of targeted therapeutics., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aims: To investigate the impact of fertility control efforts on reducing fertility and to study the contributory role of fertility inhibiting factors viz, age of the marriage, breast feeding and post-partum amenorrhea, abortion and use of contraceptives in selected area in Karachi, Pakistan. The aim was to estimate the gap between knowledge of contraceptives and its practice i.e. KAP-GAP as well as to determine the level of unmet need in the PIB colony in Karachi., Data Source: A sample survey was conducted in PIB colony in Karachi from October 2005 to November 2005 by interviewing 340 married women in reproductive ages. The data was tabulated and John Bongaarts technique was used to analyse the success of fertility control efforts in the selected area., Results: Of the total of 340 respondents, 38% were currently using contraceptive methods with 26% using OCP's and 12% were condom users. A slight reduction in total fertility (TFR) was noticed., Conclusion: The population policy of Pakistan envisages achieving population stabilization in 2020 by reducing the annual rate of population growth from 1.9% to 1.3% and TFR at 2.1. This target requires strenuous efforts to make the concept of small family an accepted milieu through an eagerly designed communication and education campaign. Concentration on proximate determinants of fertility particularly breast feeding and prolonging birth interval will not generate opposition from the community because these concepts are in accordance with Islamic injunctions and teachings.